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Chakraborty A, Kamat SS. Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases. Chem Rev 2024; 124:5470-5504. [PMID: 38607675 DOI: 10.1021/acs.chemrev.3c00701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2024]
Abstract
Lysophosphatidylserine (lyso-PS) has emerged as yet another important signaling lysophospholipid in mammals, and deregulation in its metabolism has been directly linked to an array of human autoimmune and neurological disorders. It has an indispensable role in several biological processes in humans, and therefore, cellular concentrations of lyso-PS are tightly regulated to ensure optimal signaling and functioning in physiological settings. Given its biological importance, the past two decades have seen an explosion in the available literature toward our understanding of diverse aspects of lyso-PS metabolism and signaling and its association with human diseases. In this Review, we aim to comprehensively summarize different aspects of lyso-PS, such as its structure, biodistribution, chemical synthesis, and SAR studies with some synthetic analogs. From a biochemical perspective, we provide an exhaustive coverage of the diverse biological activities modulated by lyso-PSs, such as its metabolism and the receptors that respond to them in humans. We also briefly discuss the human diseases associated with aberrant lyso-PS metabolism and signaling and posit some future directions that may advance our understanding of lyso-PS-mediated mammalian physiology.
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Affiliation(s)
- Arnab Chakraborty
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune 411008, Maharashtra, India
| | - Siddhesh S Kamat
- Department of Biology, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pashan, Pune 411008, Maharashtra, India
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2
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Li J, Huang Y, Zhang Y, Liu P, Liu M, Zhang M, Wu R. S1P/S1PR signaling pathway advancements in autoimmune diseases. BIOMOLECULES & BIOMEDICINE 2023; 23:922-935. [PMID: 37504219 PMCID: PMC10655875 DOI: 10.17305/bb.2023.9082] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 07/06/2023] [Accepted: 07/06/2023] [Indexed: 07/29/2023]
Abstract
Sphingosine-1-phosphate (S1P) is a versatile sphingolipid that is generated through the phosphorylation of sphingosine by sphingosine kinase (SPHK). S1P exerts its functional effects by binding to the G protein-coupled S1P receptor (S1PR). This lipid mediator plays a pivotal role in various cellular activities. The S1P/S1PR signaling pathway is implicated in the pathogenesis of immune-mediated diseases, significantly contributing to the functioning of the immune system. It plays a crucial role in diverse physiological and pathophysiological processes, including cell survival, proliferation, migration, immune cell recruitment, synthesis of inflammatory mediators, and the formation of lymphatic and blood vessels. However, the full extent of the involvement of this signaling pathway in the development of autoimmune diseases remains to be fully elucidated. Therefore, this study aims to comprehensively review recent research on the S1P/S1PR axis in diseases related to autoimmunity.
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Affiliation(s)
- Jianbin Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yiping Huang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yueqin Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Pengcheng Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Mengxia Liu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Min Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Rui Wu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Kumar A, Smith PJ. Horizon scanning: new and future therapies in the management of inflammatory bowel disease. EGASTROENTEROLOGY 2023; 1:e100012. [PMID: 39944001 PMCID: PMC11731077 DOI: 10.1136/egastro-2023-100012] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 09/15/2023] [Indexed: 01/02/2025]
Abstract
The current mainstay treatment modalities for inflammatory bowel disease (IBD) include immunomodulators (methotrexate and thiopurines), biologics (antitumour necrosis factor alpha (TNF-α) being the most commonly used) and other monoclonal antibodies such as the anti-integrins and anti-interleukins (IL-12/23). While ideally treatment should be initiated early in the disease process to avoid relapses and complications, the major recurring issue continues to be primary and secondary loss of response, with often 'diminishing returns' in terms of efficacy for the next line of therapies prescribed for patients with IBD. Additional concerns include the long-term risk factors such as malignancy and susceptibility to infections. Recently, there has been an influx of new and emerging medications entering the market that are showing promising efficacy results in patients with moderate-to-severe disease who have previously failed to respond to multiple drugs. This review will focus on these novel and emerging therapies-in essence, 'horizon scanning'-which includes the antiadhesion agents, cytokine inhibitors, Janus kinase inhibitors, phosphodiesterase inhibitors, sphingosine-1 phosphate receptor modulators and MicroRNA-124 (miR-124) upregulators.
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Affiliation(s)
- Aditi Kumar
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Philip J Smith
- Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
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Shanbhag K, Sharma K, Kamat SS. Photoreactive bioorthogonal lipid probes and their applications in mammalian biology. RSC Chem Biol 2023; 4:37-46. [PMID: 36685253 PMCID: PMC9811504 DOI: 10.1039/d2cb00174h] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 11/24/2022] [Indexed: 12/14/2022] Open
Abstract
Lipids are an important class of biological molecules that possess many critical physiological functions, which enable the optimal survival of all organisms, including humans. While the role of lipids in the formation of biological cellular membranes and as a source of energy is fairly well understood, the cellular signalling pathways that lipids modulate in mammals are, in comparison, poorly characterized mechanistically and/or largely unknown. In an effort to dissect these mammalian cellular pathways regulated by signalling lipids and map hitherto unknown protein-lipid interactions, the last two decades have seen tremendous progress in the development of multifunctional lipid probes that, in conjunction with well-established bioorthogonal chemistries and chemoproteomics platforms, has almost exponentially expanded our knowledge in this field. In this review, we focus on the various photoreactive bioorthogonal lipid probes described in the literature, and briefly summarize the different photo-crosslinking groups and bioorthogonal chemistries used by them. Furthermore, we report specific case examples of such photoreactive bioorthogonal lipid probes, and discuss the new biological pathways and insights that have emerged from their use through chemoproteomics in mammalian cells. Finally, we highlight the challenges associated with the use of lipid probes in biological systems, and highlight their importance in the discovery and mechanistic understanding of lipid signalling pathways in the years to come.
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Affiliation(s)
- Karthik Shanbhag
- Department of Biology, Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan Pune 411008 Maharashtra India
| | - Kavita Sharma
- Department of Biology, Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan Pune 411008 Maharashtra India
| | - Siddhesh S Kamat
- Department of Biology, Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan Pune 411008 Maharashtra India
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Hwang I, Lee SW, Oh J, Lee S, Jang IJ, Yu KS. Dose-dependent reduction of lymphocyte count and heart rate after multiple administration of LC51-0255, a novel sphingosine-1-phosphate receptor 1 modulator, in healthy subjects. Front Pharmacol 2022; 13:930615. [PMID: 36071831 PMCID: PMC9442045 DOI: 10.3389/fphar.2022.930615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
Aim: Sphingosine-1-phosphate receptor mediates the egress of lymphocytes from lymphoid organs, and its inhibition results in a decreased number of circulating lymphocytes. The aim of the current study was to investigate the safety and pharmacodynamic and pharmacokinetic characteristics of a novel sphingosine-1-phosphate receptor modulator, LC51-0255.Methods: A phase 1 randomized, double-blind, placebo-controlled, multiple dosing, dose-escalation study was conducted on healthy Korean male subjects.Results: After single and daily administration of LC51-0255 for 21 days, a dose-dependent decrease in lymphocyte count and heart rate was observed through 0.25–2 mg dose range of LC51-0255. The mean elimination half-life of LC51-0255 was 76–95 h. LC51-0255 was accumulated with a mean accumulation ratio of 5.17–6.64. During the study, LC51-0255 was generally well tolerated. The most common treatment-emergent adverse event was bradycardia. No clinically significant event of arrhythmia, including AV block, was observed. No clinically significant difference in blood pressure was observed between the dose groups. In other safety assessments, no clinically significant abnormalities were observed, except for bradycardia.Conclusion: Daily administration of LC51-0255 in the range of 0.25–2 mg resulted in a dose-dependent reduction of lymphocyte counts and heart rate. LC51-0255 is generally safe and well tolerated in healthy volunteers.
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Affiliation(s)
- Inyoung Hwang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea
| | - Sang Won Lee
- Department of Clinical Pharmacology and Therapeutics, Hanyang University Seoul Hospital, Seoul, South Korea
| | - Jaeseong Oh
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea
| | - SeungHwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea
| | - In-Jin Jang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea
- *Correspondence: Kyung-Sang Yu,
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Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy. Int J Mol Sci 2022; 23:ijms23147806. [PMID: 35887154 PMCID: PMC9324343 DOI: 10.3390/ijms23147806] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/08/2022] [Accepted: 07/11/2022] [Indexed: 02/04/2023] Open
Abstract
Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.
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Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases. Nat Rev Rheumatol 2022; 18:335-351. [PMID: 35508810 DOI: 10.1038/s41584-022-00784-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2022] [Indexed: 02/07/2023]
Abstract
Sphingosine 1-phosphate (S1P), which acts via G protein-coupled S1P receptors (S1PRs), is a bioactive lipid essential for vascular integrity and lymphocyte trafficking. The S1P-S1PR signalling axis is a key component of the inflammatory response in autoimmune rheumatic diseases. Several drugs that target S1PRs have been approved for the treatment of multiple sclerosis and inflammatory bowel disease and are under clinical testing for patients with systemic lupus erythematosus (SLE). Preclinical studies support the hypothesis that targeting the S1P-S1PR axis would be beneficial to patients with SLE, rheumatoid arthritis (RA) and systemic sclerosis (SSc) by reducing pathological inflammation. Whereas most preclinical research and development efforts are focused on reducing lymphocyte trafficking, protective effects of circulating S1P on endothelial S1PRs, which maintain the vascular barrier and enable blood circulation while dampening leukocyte extravasation, have been largely overlooked. In this Review, we take a holistic view of S1P-S1PR signalling in lymphocyte and vascular pathobiology. We focus on the potential of S1PR modulators for the treatment of SLE, RA and SSc and summarize the rationale, pathobiology and evidence from preclinical models and clinical studies. Improved understanding of S1P pathobiology in autoimmune rheumatic diseases and S1PR therapeutic modulation is anticipated to lead to efficacious and safer management of these diseases.
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8
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Choden T, Cohen NA, Rubin DT. Sphingosine-1 Phosphate Receptor Modulators: The Next Wave of Oral Therapies in Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2022; 18:265-271. [PMID: 36397756 PMCID: PMC9666818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The armamentarium of medical therapy for inflammatory bowel disease (IBD) has expanded significantly during the past decade. A major change has been the introduction of novel, orally targeted, small molecule therapies, which are promising alternatives to traditional biomolecular drugs. Sphingosine-1 phosphate (S1P) receptor-modulating therapies are the newest class of oral small molecules to be approved by the US Food and Drug Administration (FDA) for the treatment of ulcerative colitis (UC) and are currently being studied in Crohn's disease. They work by targeting the interaction between S1P and S1P1 receptors, which regulate lymphocyte egress from the spleen and lymph nodes into the systemic circulation, thereby reducing intestinal inflammation in IBD. In May 2021, ozanimod was the first S1P receptor modulator approved by the FDA for the treatment of moderately to severely active UC. This article summarizes the mechanism of action, efficacy, and safety of S1P receptor modulators based on currently available clinical studies as well as examines practical considerations and positioning in treating patients with UC.
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Affiliation(s)
- Tenzin Choden
- The University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois
| | - Nathaniel Aviv Cohen
- The University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois
| | - David T Rubin
- The University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois
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Sandhu G, Thelma BK. New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology. Front Immunol 2022; 13:834247. [PMID: 35265082 PMCID: PMC8899708 DOI: 10.3389/fimmu.2022.834247] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/31/2022] [Indexed: 12/19/2022] Open
Abstract
Rheumatoid arthritis (RA) is a multifactorial autoimmune disease characterized by chronic inflammation and destruction of multiple small joints which may lead to systemic complications. Altered immunity via pathogenic autoantibodies pre-date clinical symptom development by several years. Incompletely understood range of mechanisms trigger joint-homing, leading to clinically evident articular disease. Advances in therapeutic approaches and understanding pathogenesis have improved prognosis and likely remission. However, partial/non-response to conventional and biologic therapies witnessed in a subset of patients highlights the need for new therapeutics. It is now evident that joint disease chronicity stems from recalcitrant inflammatory synovial environment, majorly maintained by epigenetically and metabolically reprogrammed synoviocytes. Therefore, interference with effector functions of activated cell types seems a rational strategy to reinstate synovial homeostasis and complement existing anti-inflammatory interventions to mitigate chronic RA. Presenting this newer aspect of fibroblast-like synoviocytes and myeloid cells underlying the altered synovial biology in RA and its potential for identification of new druggable targets is attempted in this review. Major leads from i) molecular insights of pathogenic cell types from hypothesis free OMICS approaches; ii) hierarchy of their dysregulated signaling pathways; and iii) knowledge of druggability of molecular nodes in these pathways are highlighted. Development of such synovial biology-directed therapeutics hold promise for an enriched drug repertoire for RA.
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Affiliation(s)
| | - B. K. Thelma
- Department of Genetics, University of Delhi, New Delhi, India
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10
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Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms222111682. [PMID: 34769112 PMCID: PMC8584226 DOI: 10.3390/ijms222111682] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/20/2021] [Accepted: 10/27/2021] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic inflammation within the gastrointestinal (GI) tract. Despite the significant progress in understanding the etiology and development of treatment strategies, IBD remain incurable for thousands of patients. Metabolic deregulation is indicative of IBD, including substantial shifts in lipid metabolism. Recent data showed that changes in some phospholipids are very common in IBD patients. For instance, phosphatidylcholine (PC)/phosphatidylethanolamine (PE) and lysophosphatidylcholine (LPC)/PC ratios are associated with the severity of the inflammatory process. Composition of phospholipids also changes upon IBD towards an increase in arachidonic acid and a decrease in linoleic and a-linolenic acid levels. Moreover, an increase in certain phospholipid metabolites, such as lysophosphatidylcholine, sphingosine-1-phosphate and ceramide, can result in enhanced intestinal inflammation, malignancy, apoptosis or necroptosis. Because some phospholipids are associated with pathogenesis of IBD, they may provide a basis for new strategies to treat IBD. Current attempts are aimed at controlling phospholipid and fatty acid levels through the diet or via pharmacological manipulation of lipid metabolism.
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Tian J, Huang T, Chang S, Wang Y, Fan W, Ji H, Wang J, Yang J, Kang J, Zhou Y. Role of sphingosine-1-phosphate mediated signalling in systemic lupus erythematosus. Prostaglandins Other Lipid Mediat 2021; 156:106584. [PMID: 34352381 DOI: 10.1016/j.prostaglandins.2021.106584] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 07/02/2021] [Accepted: 07/26/2021] [Indexed: 12/17/2022]
Abstract
Systemic lupus erythematosus (SLE) is a highly prevalent autoimmune disease characterized by the malfunction of the immune system and the persistent presence of an inflammatory environment. Multiple organs can be affected during SLE, leading to heterogeneous manifestations, which eventually result in the death of patients. Due to the lack of understanding regarding the pathogenesis of SLE, the currently available treatments remain suboptimal. Sphingosine-1-phosphate (S1P) is a central bioactive lipid of sphingolipid metabolism, which serves a pivotal role in regulating numerous physiological and pathological processes. As a well-recognized regulator of lymphocyte trafficking, S1P has been shown to be closely associated with autoimmune diseases, including SLE. Importantly, S1P levels have been found to be elevated in patients with SLE. In murine models of lupus, the increased levels of S1P also contribute to disease activity and organ impairment. Moreover, data from several studies also support the hypothesis that S1P receptors and its producer-sphingosine kinases (SPHK) may serve as the potential targets for the treatment of SLE and its co-morbidities. Given the significant success that intervening with S1P signaling has achieved in treating multiple sclerosis, further exploration of its role in SLE is necessary. Therefore, the aim of the present review is to summarize the recent advances in understanding the potential mechanism by which S1P influences SLE, with a primary focus on its role in immune regulation and inflammatory responses.
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Affiliation(s)
- Jihua Tian
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China.
| | - Taiping Huang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sijia Chang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yanhong Wang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Weiping Fan
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - He Ji
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Juanjuan Wang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jia Yang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jing Kang
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yun Zhou
- Department of Nephrology, The Affiliated People's Hospital of Shanxi Medical University, Shanxi Provincial People's Hospital, Shanxi Kidney Disease Institute, Taiyuan, Shanxi, China.
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12
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Khandelwal N, Shaikh M, Mhetre A, Singh S, Sajeevan T, Joshi A, Balaji KN, Chakrapani H, Kamat SS. Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs. Cell Chem Biol 2021; 28:1169-1179.e6. [PMID: 33571455 PMCID: PMC7611549 DOI: 10.1016/j.chembiol.2021.01.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/30/2020] [Accepted: 01/06/2021] [Indexed: 12/23/2022]
Abstract
In humans, lysophosphatidylserines (lyso-PSs) are potent lipid regulators of important immunological processes. Given their structural diversity and commercial paucity, here we report the synthesis of methyl esters of lyso-PS (Me-lyso-PSs) containing medium- to very-long-chain (VLC) lipid tails. We show that Me-lyso-PSs are excellent substrates for the lyso-PS lipase ABHD12, and that these synthetic lipids are acted upon by cellular carboxylesterases to produce lyso-PSs. Next, in macrophages we demonstrate that VLC lyso-PSs orchestrate pro-inflammatory responses and in turn neuroinflammation via a Toll-like receptor 2 (TLR2)-dependent pathway. We also show that long-chain (LC) lyso-PSs robustly induce intracellular cyclic AMP production, cytosolic calcium influx, and phosphorylation of the nodal extracellular signal-regulated kinase to regulate macrophage activation via a TLR2-independent pathway. Finally, we report that LC lyso-PSs potently elicit histamine release during the mast cell degranulation process, and that ABHD12 is the major lyso-PS lipase in these immune cells.
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Affiliation(s)
- Neha Khandelwal
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Minhaj Shaikh
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Amol Mhetre
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India.
| | - Shubham Singh
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Theja Sajeevan
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | - Alaumy Joshi
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India
| | | | - Harinath Chakrapani
- Department of Chemistry, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India.
| | - Siddhesh S Kamat
- Department of Biology, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India.
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13
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Vejux A, Ghzaiel I, Nury T, Schneider V, Charrière K, Sghaier R, Zarrouk A, Leoni V, Moreau T, Lizard G. Oxysterols and multiple sclerosis: Physiopathology, evolutive biomarkers and therapeutic strategy. J Steroid Biochem Mol Biol 2021; 210:105870. [PMID: 33684483 DOI: 10.1016/j.jsbmb.2021.105870] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/02/2021] [Indexed: 12/13/2022]
Abstract
Multiple sclerosis is an autoimmune disease that affects the central nervous system. Dysfunction of the immune system leads to lesions that cause motor, sensory, cognitive, visual and/or sphincter disturbances. In the long term, these disorders can progress towards an irreversible handicap. The diagnosis takes time because there are no specific criteria to diagnose multiple sclerosis. To realize the diagnosis, a combination of clinical, biological, and radiological arguments is therefore required. Hence, there is a need to identify multiple sclerosis biomarkers. Some biomarkers target immunity through the detection of oligoclonal bands, the measurement of the IgG index and cytokines. During the physiopathological process, the blood-brain barrier can be broken, and this event can be identified by measuring metalloproteinase activity and diffusion of gadolinium in the brain by magnetic resonance imaging. Markers of demyelination and of astrocyte and microglial activity may also be of interest as well as markers of neuronal damage and mitochondrial status. The measurement of different lipids in the plasma and cerebrospinal fluid can also provide suitable information. These different lipids include fatty acids, fatty acid peroxidation products, phospholipids as well as oxidized derivatives of cholesterol (oxysterols). Oxysterols could constitute new biomarkers providing information on the form of multiple sclerosis, the outcome of the disease and the answer to treatment.
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Affiliation(s)
- Anne Vejux
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), University Bourgogne Franche-Comté, Inserm, Dijon, France.
| | - Imen Ghzaiel
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), University Bourgogne Franche-Comté, Inserm, Dijon, France; Faculty of Medicine, LR12ES05, Lab-NAFS "Nutrition - Functional Food & Vascular Health", University of Monastir, Monastir, Tunisia
| | - Thomas Nury
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), University Bourgogne Franche-Comté, Inserm, Dijon, France
| | - Vincent Schneider
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), University Bourgogne Franche-Comté, Inserm, Dijon, France; University Hospital, Department of Neurology, Dijon, France
| | - Karine Charrière
- Centre Hospitalier Universitaire de Besançon, Centre d'Investigation Clinique, INSERM CIC 1431, 25030, Besançon Cedex, France
| | - Randa Sghaier
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), University Bourgogne Franche-Comté, Inserm, Dijon, France
| | - Amira Zarrouk
- Faculty of Medicine, LR12ES05, Lab-NAFS "Nutrition - Functional Food & Vascular Health", University of Monastir, Monastir, Tunisia; Laboratory of Biochemistry, Faculty of Medicine, University of Sousse, Sousse, Tunisia
| | - Valerio Leoni
- Laboratory of Clinical Chemistry, Hospital of Varese, ASST-Settelaghi, Varese, Italy
| | - Thibault Moreau
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), University Bourgogne Franche-Comté, Inserm, Dijon, France; University Hospital, Department of Neurology, Dijon, France
| | - Gérard Lizard
- Team Bio-PeroxIL, "Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism" (EA7270), University Bourgogne Franche-Comté, Inserm, Dijon, France.
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Pérez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs 2021; 81:985-1002. [PMID: 33983615 PMCID: PMC8116828 DOI: 10.1007/s40265-021-01528-8] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2021] [Indexed: 12/12/2022]
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.
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Affiliation(s)
- Tamara Pérez-Jeldres
- Pontificia Universidad Católica de Chile, Santiago, Chile
- Hospital San Borja-Arriarán, Santiago, Chile
| | - Manuel Alvarez-Lobos
- Pontificia Universidad Católica de Chile, Santiago, Chile
- Hospital San Borja-Arriarán, Santiago, Chile
| | - Jesús Rivera-Nieves
- San Diego VA Medical Center (SDVAMC), San Diego, CA, USA.
- Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive Bldg. BRF-II Rm. 4A32, San Diego, CA, 92093-0063, USA.
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15
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Agnihotri P, Monu, Ramani S, Chakraborty D, Saquib M, Biswas S. Differential Metabolome in Rheumatoid Arthritis: a Brief Perspective. Curr Rheumatol Rep 2021; 23:42. [PMID: 33913028 DOI: 10.1007/s11926-021-00989-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Rheumatoid arthritis (RA) is a chronic autoimmune, inflammatory disease of the synovium that affects the movable joints. It develops due to the infiltration and invasion of the synovial joints by immune cells. Metabolism is anabolic or catabolic chemical reactions occurring in a cell. The biochemical pathways in synovial and immune cells are altered affecting the downstream metabolite formation. Changes in the metabolite levels alter signaling cascades which further intensify the disease. Despite current knowledge of metabolomics, there remain certain features that need to be elucidated to correlate the differential metabolite levels with RA. RECENT FINDINGS Metabolite profiling can be used to find altered patterns of metabolites in RA. Glucose, lipid, amino acid, and estrogen metabolism are the key pathways that are altered and contribute to the aggravation of RA. The altered metabolic pathways involved in different cells in RA results in complex interactions between metabolites and biomacromolecules; thus, it generates autoantigens. Moreover, understanding the correlation between differential metabolites and disease severity might help reveal potential new biomarkers and therapeutic targets for RA pathogenesis. So, considering the multi-faceted role of altered metabolites in the pathogenesis of RA, metabolic pathways of different cells are needed to be studied for a better understanding of their functions in the disease and thus, improving the present therapeutic strategies.
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Affiliation(s)
- Prachi Agnihotri
- Council of Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Mall Road, Delhi University Campus, Delhi, 110007, India
| | - Monu
- Council of Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Mall Road, Delhi University Campus, Delhi, 110007, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sheetal Ramani
- Council of Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Mall Road, Delhi University Campus, Delhi, 110007, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Debolina Chakraborty
- Council of Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Mall Road, Delhi University Campus, Delhi, 110007, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Mohd Saquib
- Council of Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Mall Road, Delhi University Campus, Delhi, 110007, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sagarika Biswas
- Council of Industrial Research (CSIR)-Institute of Genomics and Integrative Biology, Mall Road, Delhi University Campus, Delhi, 110007, India.
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16
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Pepe G, Cotugno M, Marracino F, Giova S, Capocci L, Forte M, Stanzione R, Bianchi F, Marchitti S, Di Pardo A, Sciarretta S, Rubattu S, Maglione V. Differential Expression of Sphingolipid Metabolizing Enzymes in Spontaneously Hypertensive Rats: A Possible Substrate for Susceptibility to Brain and Kidney Damage. Int J Mol Sci 2021; 22:ijms22073796. [PMID: 33917593 PMCID: PMC8038804 DOI: 10.3390/ijms22073796] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/29/2021] [Accepted: 04/01/2021] [Indexed: 02/07/2023] Open
Abstract
Alterations in the metabolism of sphingolipids, a class of biologically active molecules in cell membranes with direct effect on vascular homeostasis, are increasingly recognized as important determinant in different vascular disorders. However, it is not clear whether sphingolipids are implicated in the pathogenesis of hypertension-related cerebrovascular and renal damage. In this study, we evaluated the existence of possible abnormalities related to the sphingolipid metabolism in the brain and kidneys of two well validated spontaneously hypertensive rat strains, the stroke-prone (SHRSP) and the stroke-resistant (SHRSR) models, as compared to the normotensive Wistar Kyoto (WKY) rat strain. Our results showed a global alteration in the metabolism of sphingolipids in both cerebral and renal tissues of both hypertensive strains as compared to the normotensive rat. However, few defects, such as reduced expression of enzymes involved in the metabolism/catabolism of sphingosine-1-phosphate and in the de novo biosynthetic pathways, were exclusively detected in the SHRSP. Although further studies are necessary to fully understand the significance of these findings, they suggest that defects in specific lipid molecules and/or their related metabolic pathways may likely contribute to the pathogenesis of hypertensive target organ damage and may eventually serve as future therapeutic targets to reduce the vascular consequences of hypertension.
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Affiliation(s)
- Giuseppe Pepe
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Maria Cotugno
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Federico Marracino
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Susy Giova
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Luca Capocci
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Maurizio Forte
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Rosita Stanzione
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Franca Bianchi
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Simona Marchitti
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
| | - Alba Di Pardo
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
- Correspondence: (A.D.P.); (S.R.); (V.M.)
| | - Sebastiano Sciarretta
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina 04100, Italy;
| | - Speranza Rubattu
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
- Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University, Rome 00185, Italy
- Correspondence: (A.D.P.); (S.R.); (V.M.)
| | - Vittorio Maglione
- IRCCS Neuromed, Pozzilli 86077, Italy; (G.P.); (M.C.); (F.M.); (S.G.); (L.C.); (M.F.); (R.S.); (F.B.); (S.M.)
- Correspondence: (A.D.P.); (S.R.); (V.M.)
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17
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Qu X, Zhang Z, Xu X, Wang J, Lei C, Zhou G, Wu W, Huang L, Chen X, Yu S, Wang T. Selective sphingosine-1-phosphate receptor 1 modulation ameliorates TBI-induced neurological deficit after CCI. Neurosci Lett 2021; 750:135748. [PMID: 33610668 DOI: 10.1016/j.neulet.2021.135748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 02/09/2021] [Accepted: 02/15/2021] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND PURPOSE The inflammatory response after traumatic brain injury (TBI) can contribute to secondary brain injury. RP101075, a sphingosine-1-phosphate receptor modulator, can attenuate various inflammatory responses. Here, we hypothesized that consecutive administration of RP101075 over 3 days could broadly suppress the TBI-induced inflammatory response and ameliorate the outcomes of TBI. METHODS AND RESULTS Young C57/BL6 mice were subjected to a controlled cortical impact (CCI) model. RP101075-treated mice exhibited significantly reduced scores on the modified neurological severity score (mNSS) test on days 3, 7, 14, and 21 after TBI, in comparison to TBI mice that received the vehicle. RP101075-treated mice had a remarkably decreased percentage of foot faults on the foot fault test on days 7, 14, and 21 after surgery, in comparison to TBI mice that received the vehicle. Using the wet brain weight/dry brain weight method, we found that RP101075 attenuated brain edema at 3 days post-TBI. According to the results of the Morris water maze (MWM), TBI mice treated with RP101075 exhibited reduced latency time and an increased percentage of target quadrant time from day 24 to day 25 after TBI, in comparison to TBI mice that received the vehicle. In addition, flow cytometry and immunohistochemistry showed that RP101075 markedly decreased the number of infiltrated T cells, B cells and NK cells at 3 days after TBI. Analysis of Western blot data showed that RP101075 lowered the expression of proinflammatory factors on day 3 after TBI. CONCLUSIONS Our study demonstrated that consecutive administration of RP101075 over 3 days suppressed the TBI-induced inflammatory response and ameliorated neurological deficits after TBI. Thus, this procedure may be a potential treatment strategy for TBI in the clinical setting.
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Affiliation(s)
- Xingguang Qu
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Zhaohui Zhang
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Xiaoyun Xu
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Jiahui Wang
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Chao Lei
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Gaosheng Zhou
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Wen Wu
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Lin Huang
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Xing Chen
- Department of Critical Care Medicine, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Su Yu
- Institute of Neurology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
| | - Tao Wang
- Institute of Neurology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, Hubei, 443003, China.
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18
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A peptide immunoaffinity LC-MS/MS strategy for quantifying the GPCR protein, S1PR1 in human colon biopsies. Bioanalysis 2020; 12:1311-1324. [PMID: 32945691 DOI: 10.4155/bio-2020-0115] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Background: S1PR1, a G protein-coupled receptor (GPCR) protein, is a therapeutic target for treatment of autoimmune diseases. As a potential biomarker for drug effect and patient stratification, it is of great significance to measure it in biological samples. However, due to the hydrophobic nature of S1PR1 and the difficulties in extraction and solubilization, as well as low expression levels, quantitative determination of S1PR1 remains challenging. Results: In this work, a peptide immunoaffinity LC-MS/MS method was developed to quantify S1PR1 in biopsy-sized colon samples with an LLOQ of 7.81 pM. Conclusion: Peptide immunoaffinity LC-MS/MS based strategy has achieved the desired sensitivity for low abundance S1PR1, and the same strategy could be applied to quantify S1PR1 in multiple species and other GPCR proteins.
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19
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Xiao Z, Yang MG, Dhar TGM, Xiao HY, Gilmore JL, Marcoux D, McIntyre KW, Taylor TL, Shi H, Levesque PC, Marino AM, Cornelius G, Mathur A, Shen DR, Cvijic ME, Lehman-McKeeman LD, Sun H, Xie JH, Carter PH, Dyckman AJ. Aryl Ether-Derived Sphingosine-1-Phosphate Receptor (S1P 1) Modulators: Optimization of the PK, PD, and Safety Profiles. ACS Med Chem Lett 2020; 11:1766-1772. [PMID: 32944145 DOI: 10.1021/acsmedchemlett.0c00333] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 08/11/2020] [Indexed: 12/14/2022] Open
Abstract
Efforts aimed at increasing the in vivo potency and reducing the elimination half-life of 1 and 2 led to the identification of aryl ether and thioether-derived bicyclic S1P1 differentiated modulators 3-6. The effects of analogs 3-6 on lymphocyte reduction in the rat (desired pharmacology) along with pulmonary- and cardiovascular-related effects (undesired pharmacology) are described. Optimization of the overall properties in the aryl ether series yielded 3d, and the predicted margin of safety against the cardiovascular effects of 3d would be large enough for human studies. Importantly, compared to 1 and 2, compound 3d had a better profile in both potency (ED50 < 0.05 mg/kg) and predicted human half-life (t 1/2 ∼ 5 days).
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Affiliation(s)
- Zili Xiao
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Michael G. Yang
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - T. G. Murali Dhar
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Hai-Yun Xiao
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - John L. Gilmore
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - David Marcoux
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Kim W. McIntyre
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Tracy L. Taylor
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Hong Shi
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Paul C. Levesque
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Anthony M. Marino
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Georgia Cornelius
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Arvind Mathur
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Ding Ren Shen
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Mary Ellen Cvijic
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Lois D. Lehman-McKeeman
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Huadong Sun
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Jenny H. Xie
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Percy H. Carter
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
| | - Alaric J. Dyckman
- Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey 08543-4000, United States
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20
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The Lysophosphatidylserines-An Emerging Class of Signalling Lysophospholipids. J Membr Biol 2020; 253:381-397. [PMID: 32767057 DOI: 10.1007/s00232-020-00133-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 07/24/2020] [Indexed: 12/30/2022]
Abstract
Lysophospholipids are potent hormone-like signalling biological lipids that regulate many important biological processes in mammals (including humans). Lysophosphatidic acid and sphingosine-1-phosphate represent the best studied examples for this lipid class, and their metabolic enzymes and/or cognate receptors are currently under clinical investigation for treatment of various neurological and autoimmune diseases in humans. Over the past two decades, the lysophsophatidylserines (lyso-PSs) have emerged as yet another biologically important lysophospholipid, and deregulation in its metabolism has been linked to various human pathophysiological conditions. Despite its recent emergence, an exhaustive review summarizing recent advances on lyso-PSs and the biological pathways that this bioactive lysophospholipid regulates has been lacking. To address this, here, we summarize studies that led to the discovery of lyso-PS as a potent signalling biomolecule, and discuss the structure, its detection in biological systems, and the biodistribution of this lysophospholipid in various mammalian systems. Further, we describe in detail the enzymatic pathways that are involved in the biosynthesis and degradation of this lipid and the putative lyso-PS receptors reported in the literature. Finally, we discuss the various biological pathways directly regulated by lyso-PSs in mammals and prospect new questions for this still emerging biomedically important signalling lysophospholipid.
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21
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Leuti A, Fazio D, Fava M, Piccoli A, Oddi S, Maccarrone M. Bioactive lipids, inflammation and chronic diseases. Adv Drug Deliv Rev 2020; 159:133-169. [PMID: 32628989 DOI: 10.1016/j.addr.2020.06.028] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/09/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
Endogenous bioactive lipids are part of a complex network that modulates a plethora of cellular and molecular processes involved in health and disease, of which inflammation represents one of the most prominent examples. Inflammation serves as a well-conserved defence mechanism, triggered in the event of chemical, mechanical or microbial damage, that is meant to eradicate the source of damage and restore tissue function. However, excessive inflammatory signals, or impairment of pro-resolving/anti-inflammatory pathways leads to chronic inflammation, which is a hallmark of chronic pathologies. All main classes of endogenous bioactive lipids - namely eicosanoids, specialized pro-resolving lipid mediators, lysoglycerophopsholipids and endocannabinoids - have been consistently involved in the chronic inflammation that characterises pathologies such as cancer, diabetes, atherosclerosis, asthma, as well as autoimmune and neurodegenerative disorders and inflammatory bowel diseases. This review gathers the current knowledge concerning the involvement of endogenous bioactive lipids in the pathogenic processes of chronic inflammatory pathologies.
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22
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Controlling leukocyte trafficking in IBD. Pharmacol Res 2020; 159:105050. [PMID: 32598943 DOI: 10.1016/j.phrs.2020.105050] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by the accumulation of immune cells, myeloid cells and lymphocytes in the inflamed intestine. The presence and persistence of these cells, together with the production of pro-inflammatory mediators, perpetuate intestinal inflammation in both ulcerative colitis and Crohn's disease. Thus, blockade of leukocyte migration to the intestine is a main strategy used to control the disease and alleviate symptoms. Vedolizumab is the only anti-integrin drug approved for the treatment of IBD but several other drugs also targeting integrins, chemokines or receptors involved in leukocyte intestinal trafficking are under development and investigated for their efficacy and safety in IBD. The challenge now is to better understand the specific mechanism of action underlying each drug and to identify biomarkers that would guide drug selection in the individual patient.
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23
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Feng Y, Mischler WJ, Gurung AC, Kavanagh TR, Androsov G, Sadow PM, Herbert ZT, Priolo C. Therapeutic Targeting of the Secreted Lysophospholipase D Autotaxin Suppresses Tuberous Sclerosis Complex-Associated Tumorigenesis. Cancer Res 2020; 80:2751-2763. [PMID: 32393662 DOI: 10.1158/0008-5472.can-19-2884] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 03/25/2020] [Accepted: 05/05/2020] [Indexed: 12/14/2022]
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by multiorgan hamartomas, including renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM). TSC2 deficiency leads to hyperactivation of mTOR Complex 1 (mTORC1), a master regulator of cell growth and metabolism. Phospholipid metabolism is dysregulated upon TSC2 loss, causing enhanced production of lysophosphatidylcholine (LPC) species by TSC2-deficient tumor cells. LPC is the major substrate of the secreted lysophospholipase D autotaxin (ATX), which generates two bioactive lipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). We report here that ATX expression is upregulated in human renal angiomyolipoma-derived TSC2-deficient cells compared with TSC2 add-back cells. Inhibition of ATX via the clinically developed compound GLPG1690 suppressed TSC2-loss associated oncogenicity in vitro and in vivo and induced apoptosis in TSC2-deficient cells. GLPG1690 suppressed AKT and ERK1/2 signaling and profoundly impacted the transcriptome of these cells while inducing minor gene expression changes in TSC2 add-back cells. RNA-sequencing studies revealed transcriptomic signatures of LPA and S1P, suggesting an LPA/S1P-mediated reprogramming of the TSC lipidome. In addition, supplementation of LPA or S1P rescued proliferation and viability, neutral lipid content, and AKT or ERK1/2 signaling in human TSC2-deficient cells treated with GLPG1690. Importantly, TSC-associated renal angiomyolipomas have higher expression of LPA receptor 1 and S1P receptor 3 compared with normal kidney. These studies increase our understanding of TSC2-deficient cell metabolism, leading to novel potential therapeutic opportunities for TSC and LAM. SIGNIFICANCE: This study identifies activation of the ATX-LPA/S1P pathway as a novel mode of metabolic dysregulation upon TSC2 loss, highlighting critical roles for ATX in TSC2-deficient cell fitness and in TSC tumorigenesis.
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Affiliation(s)
- You Feng
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - William J Mischler
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Ashish C Gurung
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Taylor R Kavanagh
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Grigoriy Androsov
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Peter M Sadow
- Harvard Medical School, Boston, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Zachary T Herbert
- Harvard Medical School, Boston, Massachusetts
- Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Carmen Priolo
- Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
- Harvard Medical School, Boston, Massachusetts
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Abstract
There is substantial evidence that the enzymes, sphingosine kinase 1 and 2, which catalyse the formation of the bioactive lipid sphingosine 1-phosphate, are involved in pathophysiological processes. In this chapter, we appraise the evidence that both enzymes are druggable and describe how isoform-specific inhibitors can be developed based on the plasticity of the sphingosine-binding site. This is contextualised with the effect of sphingosine kinase inhibitors in cancer, pulmonary hypertension, neurodegeneration, inflammation and sickling.
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Affiliation(s)
- Susan Pyne
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , Glasgow, Scotland, UK
| | - David R Adams
- Institute of Chemical Sciences, Heriot-Watt University, Edinburgh, Scotland, UK
| | - Nigel J Pyne
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , Glasgow, Scotland, UK.
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25
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Diab J, Hansen T, Goll R, Stenlund H, Ahnlund M, Jensen E, Moritz T, Florholmen J, Forsdahl G. Lipidomics in Ulcerative Colitis Reveal Alteration in Mucosal Lipid Composition Associated With the Disease State. Inflamm Bowel Dis 2019; 25:1780-1787. [PMID: 31077307 DOI: 10.1093/ibd/izz098] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND The onset of ulcerative colitis (UC) is associated with alterations in lipid metabolism and a disruption of the balance between pro- and anti-inflammatory molecules. Only a few studies describe the mucosal lipid biosignatures during active UC. Moreover, the dynamics of lipid metabolism in the remission state is poorly defined. Therefore, this study aims to characterize mucosal lipid profiles in treatment-naïve UC patients and deep remission UC patients compared with healthy subjects. METHODS Treatment-naïve UC patients (n = 21), UC patients in deep remission (n = 12), and healthy volunteers (n = 14) were recruited. The state of deep remission was defined by histological and immunological remission defined by a normalized TNF-α gene expression. Mucosa biopsies were collected by colonoscopy. Lipid analysis was performed by means of ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS-MS). In total, 220 lipids from 11 lipid classes were identified. RESULTS The relative concentration of 122 and 36 lipids was altered in UC treatment-naïve patients and UC remission patients, respectively, compared with healthy controls. The highest number of significant variations was in the phosphatidylcholine (PC), ceramide (Cer), and sphingomyelin (SM) composition. Multivariate analysis revealed discrimination among the study groups based on the lipid profile. Furthermore, changes in phosphatidylethanolamine(38:3), Cer(d18:1/24:0), and Cer(d18:1/24:2) were most distinctive between the groups. CONCLUSION This study revealed a discriminant mucosal lipid composition pattern between treatment-naïve UC patients, deep remission UC patients, and healthy controls. We report several distinctive lipids, which might be involved in the inflammatory response in UC, and could reflect the disease state.
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Affiliation(s)
- Joseph Diab
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| | - Terkel Hansen
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| | - Rasmus Goll
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.,Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Hans Stenlund
- Swedish Metabolomics Center, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Maria Ahnlund
- Swedish Metabolomics Center, Swedish University of Agricultural Sciences, Umeå, Sweden
| | - Einar Jensen
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
| | - Thomas Moritz
- Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Jon Florholmen
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway.,Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Guro Forsdahl
- Natural Products and Medicinal Chemistry Research Group, Department of Pharmacy Faculty of Health Sciences, University of Tromsø-The Arctic University of Norway, Tromsø, Norway
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26
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Yoo JH, Donowitz M. Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases. World J Gastroenterol 2019; 25:4125-4147. [PMID: 31435168 PMCID: PMC6700704 DOI: 10.3748/wjg.v25.i30.4125] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 06/14/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
The introduction of biologics such as anti-tumor necrosis factor (TNF) monoclonal antibodies followed by anti-integrins has dramatically changed the therapeutic paradigm of inflammatory bowel diseases (IBD). Furthermore, a newly developed anti-p40 subunit of interleukin (IL)-12 and IL-23 (ustekinumab) has been recently approved in the United States for patients with moderate to severe Crohn’s disease who have failed treatment with anti-TNFs. However, these immunosuppressive therapeutics which focus on anti-inflammatory mechanisms or immune cells still fail to achieve long-term remission in a significant percentage of patients. This strongly underlines the need to identify novel treatment targets beyond immune suppression to treat IBD. Recent studies have revealed the critical role of intestinal epithelial cells (IECs) in the pathogenesis of IBD. Physical, biochemical and immunologic driven barrier dysfunctions of epithelial cells contribute to the development of IBD. In addition, the recent establishment of adult stem cell-derived intestinal enteroid/organoid culture technology has allowed an exciting opportunity to study human IECs comprising all normal epithelial cells. This long-term epithelial culture model can be generated from endoscopic biopsies or surgical resections and recapitulates the tissue of origin, representing a promising platform for novel drug discovery in IBD. This review describes the advantages of intestinal enteroids/organoids as a research tool for intestinal diseases, introduces studies with these models in IBD, and gives a description of the current status of therapeutic approaches in IBD. Finally, we provide an overview of the current endeavors to identify a novel drug target for IBD therapy based on studies with human enteroids/organoids and describe the challenges in using enteroids/organoids as an IBD model.
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Affiliation(s)
- Jun-Hwan Yoo
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam 13496, South Korea
| | - Mark Donowitz
- Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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27
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Di Pardo A, Pepe G, Castaldo S, Marracino F, Capocci L, Amico E, Madonna M, Giova S, Jeong SK, Park BM, Park BD, Maglione V. Stimulation of Sphingosine Kinase 1 (SPHK1) Is Beneficial in a Huntington's Disease Pre-clinical Model. Front Mol Neurosci 2019; 12:100. [PMID: 31068790 PMCID: PMC6491579 DOI: 10.3389/fnmol.2019.00100] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 04/03/2019] [Indexed: 12/19/2022] Open
Abstract
Although several agents have been identified to provide therapeutic benefits in Huntington disease (HD), the number of conventionally used treatments remains limited and only symptomatic. Thus, it is plausible that the need to identify new therapeutic targets for the development of alternative and more effective treatments is becoming increasingly urgent. Recently, the sphingosine-1-phosphate (S1P) axis has been reported to be a valid potential novel molecular target for therapy development in HD. Modulation of aberrant metabolism of S1P in HD has been proved to exert neuroprotective action in vitro settings including human HD iPSC-derived neurons. In this study, we investigated whether promoting S1P production by stimulating Sphingosine Kinase 1 (SPHK1) by the selective activator, K6PC-5, may have therapeutic benefit in vivo in R6/2 HD mouse model. Our findings indicate that chronic administration of 0.05 mg/kg K6PC-5 exerted an overall beneficial effect in R6/2 mice. It significantly slowed down the progressive motor deficit associated with disease progression, modulated S1P metabolism, evoked the activation of pro-survival pathways and markedly reduced the toxic mutant huntingtin (mHtt) aggregation. These results suggest that K6PC-5 may represent a future therapeutic option in HD and may potentially counteract the perturbed brain function induced by deregulated S1P pathways.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Se Kyoo Jeong
- Department of Cosmetic Science, Seowon University, Cheongju, South Korea
| | - Bu-Mahn Park
- NeoPharm USA Inc., Engelwood Cliffs, NJ, United States
| | - Byeong Deog Park
- Dr. Raymond Laboratories, Inc., Englewood Cliffs, NJ, United States
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28
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Pérez-Jeldres T, Tyler CJ, Boyer JD, Karuppuchamy T, Yarur A, Giles DA, Yeasmin S, Lundborg L, Sandborn WJ, Patel DR, Rivera-Nieves J. Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists. Front Pharmacol 2019; 10:212. [PMID: 30930775 PMCID: PMC6425155 DOI: 10.3389/fphar.2019.00212] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 02/19/2019] [Indexed: 12/11/2022] Open
Abstract
The inflammatory Bowel diseases (IBDs) are a chronic, relapsing inflammatory diseases of the gastrointestinal tract with heterogeneous behavior and prognosis. The introduction of biological therapies including anti-TNF, anti-IL-12/23, and anti-integrins, has revolutionized the treatment of IBD, but these drugs are not universally effective. Due to the complex molecular structures of biologics, they are uniformly immunogenic. New discoveries concerning the underlying mechanisms involved in the pathogenesis of IBD have allowed for progress in the development of new treatment options. The advantage of small molecules (SMs) over biological therapies includes their lack of immunogenicity, short half-life, oral administration, and low manufacturing cost. Among these, the Janus Kinases (JAKs) inhibition has emerged as a novel strategy to modulate downstream cytokine signaling during immune-mediated diseases. These drugs target various cytokine signaling pathways that participate in the pathogenesis of IBD. Tofacitinib, a JAK inhibitor targeting predominantly JAK1 and JAK3, has been approved for the treatment of ulcerative colitis (UC), and there are other specific JAK inhibitors under development that may be effective in Crohn's. Similarly, the traffic of lymphocytes can now be targeted by another SM. Sphingosine-1-phosphate receptor (S1PR) agonism is a novel strategy that acts, in part, by interfering with lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. S1PR agonists are being studied in IBD and other immune-mediated disorders. This review will focus on SM drugs approved and under development, including JAK inhibitors (tofacitinib, filgotinib, upadacitinib, peficitinib) and S1PR agonists (KRP-203, fingolimod, ozanimod, etrasimod, amiselimod), and their mechanism of action.
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Affiliation(s)
- Tamara Pérez-Jeldres
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
- Department of Medicine, Pontifical Universidad Católica de Chile, Santiago, Chile
- San Borja Arriarán Clinic Hospital, Santiago, Chile
| | - Christopher J. Tyler
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
- VA San Diego Healthcare System, San Diego, CA, United States
| | - Joshua D. Boyer
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
- VA San Diego Healthcare System, San Diego, CA, United States
| | - Thangaraj Karuppuchamy
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
- VA San Diego Healthcare System, San Diego, CA, United States
| | - Andrés Yarur
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Daniel A. Giles
- La Jolla Institute for Allergy and Immunology, San Diego, CA, United States
| | - Shaila Yeasmin
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
| | - Luke Lundborg
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
| | - William J. Sandborn
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
| | - Derek R. Patel
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
| | - Jesús Rivera-Nieves
- Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California, San Diego, La Jolla, CA, United States
- VA San Diego Healthcare System, San Diego, CA, United States
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29
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Di Pardo A, Castaldo S, Amico E, Pepe G, Marracino F, Capocci L, Giovannelli A, Madonna M, van Bergeijk J, Buttari F, van der Kam E, Maglione V. Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease. Hum Mol Genet 2019; 27:2490-2501. [PMID: 29688337 DOI: 10.1093/hmg/ddy153] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 04/19/2018] [Indexed: 12/21/2022] Open
Abstract
Huntington's disease (HD) is the most common neurodegenerative disorder for which no effective cure is yet available. Although several agents have been identified to provide benefits so far, the number of therapeutic options remains limited with only symptomatic treatment available. Over the past few years, we have demonstrated that sphingolipid-based approaches may open the door to new and more targeted treatments for the disease. In this study, we investigated the therapeutic potential of stimulating sphingosine-1-phosphate (S1P) receptor 5 by the new selective agonist A-971432 (provided by AbbVie) in R6/2 mice, a widely used HD animal model. Chronic administration of low-dose (0.1 mg/kg) A-971432 slowed down the progression of the disease and significantly prolonged lifespan in symptomatic R6/2 mice. Such beneficial effects were associated with activation of pro-survival pathways (BDNF, AKT and ERK) and with reduction of mutant huntingtin aggregation. A-971432 also protected blood-brain barrier (BBB) homeostasis in the same mice. Interestingly, when administered early in the disease, before any overt symptoms, A-971432 completely protected HD mice from the classic progressive motor deficit and preserved BBB integrity. Beside representing a promising strategy to take into consideration for the development of alternative therapeutic options for HD, selective stimulation of S1P receptor 5 may be also seen as an effective approach to target brain vasculature defects in the disease.
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Affiliation(s)
- Alba Di Pardo
- IRCCS Neuromed, Localitá Camerelle, Pozzilli (IS), Italy
| | | | - Enrico Amico
- IRCCS Neuromed, Localitá Camerelle, Pozzilli (IS), Italy
| | - Giuseppe Pepe
- IRCCS Neuromed, Localitá Camerelle, Pozzilli (IS), Italy
| | | | - Luca Capocci
- IRCCS Neuromed, Localitá Camerelle, Pozzilli (IS), Italy
| | | | | | | | - Fabio Buttari
- IRCCS Neuromed, Localitá Camerelle, Pozzilli (IS), Italy
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30
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31
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Ogasawara D, Ichu TA, Vartabedian VF, Benthuysen J, Jing H, Reed A, Ulanovskaya OA, Hulce JJ, Roberts A, Brown S, Rosen H, Teijaro JR, Cravatt BF. Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo. Nat Chem Biol 2018; 14:1099-1108. [PMID: 30420694 PMCID: PMC6263940 DOI: 10.1038/s41589-018-0155-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 09/19/2018] [Indexed: 11/09/2022]
Abstract
ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12-/- mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo-active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12-/- mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function. On the other hand, both DO264-treated and ABHD12-/- mice displayed heightened immunological responses to lymphocytic choriomeningitis virus (LCMV) clone 13 infection that manifested as severe lung pathology with elevated proinflammatory chemokines. These results reveal similarities and differences in the phenotypic impact of pharmacological versus genetic blockade of ABHD12 and point to a key role for this enzyme in regulating immunostimulatory lipid pathways in vivo.
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Affiliation(s)
- Daisuke Ogasawara
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | - Taka-Aki Ichu
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | - Vincent F Vartabedian
- Department of Immunology and Infectious Disease, The Scripps Research Institute, La Jolla, CA, USA
| | | | - Hui Jing
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | - Alex Reed
- Abide Therapeutics, San Diego, CA, USA
| | | | - Jonathan J Hulce
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | - Amanda Roberts
- Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA
| | - Steven Brown
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | - Hugh Rosen
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
| | - John R Teijaro
- Department of Immunology and Infectious Disease, The Scripps Research Institute, La Jolla, CA, USA.
| | - Benjamin F Cravatt
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
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Comi G, Hartung HP, Bakshi R, Williams IM, Wiendl H. Benefit-Risk Profile of Sphingosine-1-Phosphate Receptor Modulators in Relapsing and Secondary Progressive Multiple Sclerosis. Drugs 2018; 77:1755-1768. [PMID: 28905255 PMCID: PMC5661009 DOI: 10.1007/s40265-017-0814-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit–risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.
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Affiliation(s)
- Giancarlo Comi
- Department of Neurology and INSPE, Scientific Institute Hospital San Raffaele, Vita-Salute San Raffaele University, Milan, Italy.
| | - Hans-Peter Hartung
- Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.,Center for Neuropsychiatry, LVR Klinikum, Düsseldorf, Germany
| | | | | | - Heinz Wiendl
- Department of Neurology, University Hospital Münster, Münster, Germany
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Marciniak A, Camp SM, Garcia JGN, Polt R. An update on sphingosine-1-phosphate receptor 1 modulators. Bioorg Med Chem Lett 2018; 28:3585-3591. [PMID: 30409535 DOI: 10.1016/j.bmcl.2018.10.042] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/22/2018] [Accepted: 10/25/2018] [Indexed: 12/14/2022]
Abstract
Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P1) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P1, and an updated overview of synthetic sphingosine S1P1 agonists.
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Affiliation(s)
- Alexander Marciniak
- Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, United States.
| | - Sara M Camp
- Department of Medicine, The University of Arizona, Tucson, AZ 85724, United States.
| | - Joe G N Garcia
- Department of Medicine, The University of Arizona, Tucson, AZ 85724, United States.
| | - Robin Polt
- Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, United States.
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Gholamzad M, Ebtekar M, Ardestani MS, Azimi M, Mahmodi Z, Mousavi MJ, Aslani S. A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm Res 2018; 68:25-38. [DOI: 10.1007/s00011-018-1185-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/13/2018] [Accepted: 08/23/2018] [Indexed: 12/13/2022] Open
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Abstract
While normal angiogenesis is critical for development and tissue growth, pathological angiogenesis is important for the growth and spread of cancers by supplying nutrients and oxygen as well as providing a conduit for distant metastasis. The interaction among extracellular matrix molecules, tumor cells, endothelial cells, fibroblasts, and immune cells is critical in pathological angiogenesis, in which various angiogenic growth factors, chemokines, and lipid mediators produced from these cells as well as hypoxic microenvironment promote angiogenesis by regulating expression and/or activity of various related genes. Sphingosine 1-phosphate and lysophosphatidic acid, bioactive lipid mediators which act via specific G protein-coupled receptors, play critical roles in angiogenesis. In addition, other lipid mediators including prostaglandin E2, lipoxin, and resolvins are produced in a stimulus-dependent manner and have pro- or anti-angiogenic effects, presumably through their specific GPCRs. Dysregulated lipid mediator signaling pathways are observed in the contxt of some tumors. This review will focus on LPA and S1P, two bioactive lipid mediators in their regulation of angiogenesis and cell migration that are critical for tumor growth and spread.
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Affiliation(s)
- Yu Hisano
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States
| | - Timothy Hla
- Vascular Biology Program, Boston Children's Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States.
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Felten R, Dervovic E, Chasset F, Gottenberg JE, Sibilia J, Scher F, Arnaud L. The 2018 pipeline of targeted therapies under clinical development for Systemic Lupus Erythematosus: a systematic review of trials. Autoimmun Rev 2018; 17:781-790. [PMID: 29885544 DOI: 10.1016/j.autrev.2018.02.011] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 02/03/2018] [Indexed: 12/22/2022]
Abstract
Currently, Systemic Lupus Erythematosus (SLE) therapies range from antimalarials to glucocorticoids, in addition to immunosupressive agents or biologics such as rituximab or belimumab, when needed. Several unmet needs remain in the treatment SLE and more targeted drugs with improved safety profiles are expected. Based on recent advances in the understanding of the complex pathogenesis of SLE, several targeted treatments are currently assessed in clinical trials. In this study, we performed a systematic review of all targeted therapies under clinical development in SLE in 17 online registries of clinical trials. The search yielded a total of 1140 trials, from which we identified 74 targeted therapies for SLE. Those treatments target inflammatory cytokines, chemokines, or their receptors (n = 17), B cells or plasma cells (n = 17), intracellular signalling pathways (n = 10), T/B cells costimulation molecules (n = 8), interferons (n = 7), plasmacytoid dendritic cells (pDC) (n = 3), as well as various other targets (n = 12). Not all these candidate drugs will reach phase III, but the broad spectrum of drugs being investigated may satisfy the urgent need for improved lupus medications. The identification of biomarkers that would allow adequate prediction of response-to-therapy remains high, but when solved will allow a more rationale selection of the optimal pharmacological agent at the patient level.
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Affiliation(s)
- Renaud Felten
- Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, RESO, Laboratoire d'Immunopathologie et de Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR3572, France
| | - Elida Dervovic
- Service de Pharmacie-Stérilisation, Hôpitaux Universitaires de Strasbourg, France
| | - François Chasset
- Sorbonne Université, Faculté de Médecine Sorbonne Université, AP-HP, Service de Dermatologie et Allergologie, Hôpital Tenon, F-75020 Paris, France
| | - Jacques-Eric Gottenberg
- Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, RESO, Laboratoire d'Immunopathologie et de Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR3572, France
| | - Jean Sibilia
- Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, INSERM UMR_S1109, RESO, Université de Strasbourg, F-67000 Strasbourg, France
| | - Florence Scher
- Service de Pharmacie-Stérilisation, Hôpitaux Universitaires de Strasbourg, France
| | - Laurent Arnaud
- Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, INSERM UMR_S1109, RESO, Université de Strasbourg, F-67000 Strasbourg, France.
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37
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Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase. Neuropharmacology 2018; 135:139-150. [DOI: 10.1016/j.neuropharm.2018.02.023] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 02/14/2018] [Accepted: 02/22/2018] [Indexed: 12/14/2022]
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38
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Narayan RN, Forsthuber T, Stüve O. Emerging drugs for primary progressive multiple sclerosis. Expert Opin Emerg Drugs 2018; 23:97-110. [DOI: 10.1080/14728214.2018.1463370] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Ram Narendra Narayan
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Olaf Stüve
- Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Neurology Section, VA North Texas Health Care System, Dallas VA Medical Center, Dallas, TX, USA
- Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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39
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Cuzzocrea S, Doyle T, Campolo M, Paterniti I, Esposito E, Farr SA, Salvemini D. Sphingosine 1-Phosphate Receptor Subtype 1 as a Therapeutic Target for Brain Trauma. J Neurotrauma 2018; 35:1452-1466. [PMID: 29310513 DOI: 10.1089/neu.2017.5391] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Traumatic brain injury (TBI) provokes secondary pathological mechanisms, including ischemic and inflammatory processes. The new research in sphingosine 1-phosphate (S1P) receptor modulators has opened the door for an effective mechanism of reducing central nervous system (CNS) inflammatory lesion activity. Thus, the aim of this study was to characterize the immunomodulatory effect of the functional S1PR1 antagonist, siponimod, in phase III clinical trials for autoimmune disorders and of the competitive sphingosine 1-phosphate receptor subtype 1 (S1PR1) antagonist, TASP0277308, in pre-clinical development in an in vivo model of TBI in mice. We used the well-characterized model of TBI caused by controlled cortical impact. Mice were injected intraperitoneally with siponimod or TASP0277308 (1 mg/kg) at 1 and 4 h post-trauma. Our results demonstrated that these agents exerted significant beneficial effects on TBI pre-clinical scores in term of anti-inflammatory and immunomodulatory effects, in particular, attenuation of astrocytes and microglia activation, cytokines release, and rescue of the reduction of adhesion molecules (i.e., occludin and zonula occludens-1). Moreover, these compounds were able to decrease T-cell activation visible by reduction of CD4+ and CD8+, reduce the lesioned area (measured by 2,3,5-triphenyltetrazolium chloride staining), and to preserve tissue architecture, microtubule stability, and neural plasticity. Moreover, our findings provide pre-clinical evidence for the use of low-dose oral S1PR1 antagonists as neuroprotective strategies for TBI and broaden our understanding of the underlying S1PR1-driven neuroinflammatory processes in the pathophysiology of TBI. Altogether, our results showed that blocking the S1PR1 axis is an effective therapeutic strategy to mitigate neuropathological effects engaged in the CNS by TBI.
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Affiliation(s)
- Salvatore Cuzzocrea
- 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Viale Ferdinando Stagno D'Alcontres, Messina, Italy .,2 Department of Pharmacology and Physiology Saint Louis University , St. Louis, Missouri
| | - Timothy Doyle
- 2 Department of Pharmacology and Physiology Saint Louis University , St. Louis, Missouri
| | - Michela Campolo
- 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Viale Ferdinando Stagno D'Alcontres, Messina, Italy
| | - Irene Paterniti
- 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Viale Ferdinando Stagno D'Alcontres, Messina, Italy
| | - Emanuela Esposito
- 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Viale Ferdinando Stagno D'Alcontres, Messina, Italy
| | - Susan A Farr
- 3 VA Medical Center Saint Louis , St. Louis, Missouri.,4 Division of Geriatric Medicine, Saint Louis University , St. Louis, Missouri
| | - Daniela Salvemini
- 2 Department of Pharmacology and Physiology Saint Louis University , St. Louis, Missouri
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40
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Taylor Meadows KR, Steinberg MW, Clemons B, Stokes ME, Opiteck GJ, Peach R, Scott FL. Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus. PLoS One 2018; 13:e0193236. [PMID: 29608575 PMCID: PMC5880347 DOI: 10.1371/journal.pone.0193236] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 02/07/2018] [Indexed: 01/22/2023] Open
Abstract
Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus. Compared with vehicle-treated animals, ozanimod and RP-101075 reduced proteinuria over the duration of the study and serum blood urea nitrogen at termination. Additionally, ozanimod and RP-101075 reduced kidney disease in a dose-dependent manner, as measured by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits, and tubular atrophy. Further exploration into gene expression changes in the kidney demonstrate that RP-101075 also significantly reduced expression of fibrotic and immune-related genes in the kidneys. Of note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of interferon alpha in lupus patients, and reduced all B and T cell subsets in the spleen. Given the efficacy demonstrated by ozanimod and its metabolite RP-101075 in the NZBWF1 preclinical animal model, ozanimod may warrant clinical evaluation as a potential treatment for systemic lupus erythematosus.
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Affiliation(s)
- Kristen R. Taylor Meadows
- Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, California, United States of America
- * E-mail:
| | - Marcos W. Steinberg
- Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, California, United States of America
| | - Bryan Clemons
- Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, California, United States of America
| | | | - Gregory J. Opiteck
- Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, California, United States of America
| | - Robert Peach
- Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, California, United States of America
| | - Fiona L. Scott
- Receptos, a wholly owned subsidiary of Celgene Corporation, San Diego, California, United States of America
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41
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Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res 2018; 16:26-42. [PMID: 29422795 PMCID: PMC5797268 DOI: 10.5217/ir.2018.16.1.26] [Citation(s) in RCA: 380] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/18/2017] [Accepted: 04/19/2017] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory state of the gastrointestinal tract and can be classified into 2 main clinical phenomena: Crohn's disease (CD) and ulcerative colitis (UC). The pathogenesis of IBD, including CD and UC, involves the presence of pathogenic factors such as abnormal gut microbiota, immune response dysregulation, environmental changes, and gene variants. Although many investigations have tried to identify novel pathogenic factors associated with IBD that are related to environmental, genetic, microbial, and immune response factors, a full understanding of IBD pathogenesis is unclear. Thus, IBD treatment is far from optimal, and patient outcomes can be unsatisfactory. As result of massive studying on IBD, T helper 17 (Th17) cells and innate lymphoid cells (ILCs) are investigated on their effects on IBD. A recent study of the plasticity of Th17 cells focused primarily on colitis. ILCs also emerging as novel cell family, which play a role in the pathogenesis of IBD. IBD immunopathogenesis is key to understanding the causes of IBD and can lead to the development of IBD therapies. The aim of this review is to explain the pathogenesis of IBD, with a focus on immunological factors and therapies.
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Affiliation(s)
- Seung Hoon Lee
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Jeong eun Kwon
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
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42
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Espaillat MP, Snider AJ, Qiu Z, Channer B, Coant N, Schuchman EH, Kew RR, Sheridan BS, Hannun YA, Obeid LM. Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment. FASEB J 2017; 32:2339-2353. [PMID: 29259036 DOI: 10.1096/fj.201700585r] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Bioactive sphingolipids are modulators of immune processes and their metabolism is often dysregulated in ulcerative colitis, a major category of inflammatory bowel disease (IBD). While multiple axes of sphingolipid metabolism have been investigated to delineate mechanisms regulating ulcerative colitis, the role of acid ceramidase (AC) in intestinal inflammation is yet to be characterized. Here we demonstrate that AC expression is elevated selectively in the inflammatory infiltrate in human and murine colitis. To probe for mechanistic insight into how AC up-regulation can impact intestinal inflammation, we investigated the selective loss of AC expression in the myeloid population. Using a model of intestinal epithelial injury, we demonstrate that myeloid AC conditional knockout mice exhibit impairment of neutrophil recruitment to the colon mucosa as a result of defective cytokine and chemokine production. Furthermore, the loss of myeloid AC protects from tumor incidence in colitis-associated cancer (CAC) and inhibits the expansion of neutrophils and granulocytic myeloid-derived suppressor cells in the tumor microenvironment. Collectively, our results demonstrate a tissue-specific role for AC in regulating neutrophilic inflammation and cytokine production. We demonstrate novel mechanisms of how granulocytes are recruited to the colon that may have therapeutic potential in intestinal inflammation, IBD, and CAC.-Espaillat, M. P., Snider, A. J., Qiu, Z., Channer, B., Coant, N., Schuchman, E. H., Kew, R. R., Sheridan, B. S., Hannun, Y. A., Obeid, L. M. Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment.
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Affiliation(s)
- Mel Pilar Espaillat
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.,Department of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Ashley J Snider
- Department of Medicine, Stony Brook University, Stony Brook, New York, USA.,Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.,Northport Veterans Affairs Medical Center, Northport, New York, USA
| | - Zhijuan Qiu
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
| | - Breana Channer
- Department of Medicine, Stony Brook University, Stony Brook, New York, USA.,Department of Biology, Stony Brook University, Stony Brook, New York, USA
| | - Nicolas Coant
- Department of Medicine, Stony Brook University, Stony Brook, New York, USA
| | - Edward H Schuchman
- Plexcera Therapeutics, New York, New York, USA.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Richard R Kew
- Department of Pathology, Stony Brook University, Stony Brook, New York, USA
| | - Brian S Sheridan
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA
| | - Yusuf A Hannun
- Department of Medicine, Stony Brook University, Stony Brook, New York, USA.,Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA
| | - Lina M Obeid
- Department of Medicine, Stony Brook University, Stony Brook, New York, USA.,Stony Brook Cancer Center, Stony Brook University, Stony Brook, New York, USA.,Northport Veterans Affairs Medical Center, Northport, New York, USA
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43
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Dash RP, Srinivas NR, Rais R. A review of bioanalytical quantitative methods for selected sphingosine 1-phosphate receptor modulators. Biomed Chromatogr 2017; 32. [DOI: 10.1002/bmc.4109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/18/2017] [Accepted: 09/28/2017] [Indexed: 11/12/2022]
Affiliation(s)
- Ranjeet Prasad Dash
- Drug Metabolism and Pharmacokinetics, Johns Hopkins Drug Discovery Program; Johns Hopkins University; Baltimore Maryland USA
- Department of Neurology; Johns Hopkins University; Baltimore Maryland USA
| | | | - Rana Rais
- Drug Metabolism and Pharmacokinetics, Johns Hopkins Drug Discovery Program; Johns Hopkins University; Baltimore Maryland USA
- Department of Neurology; Johns Hopkins University; Baltimore Maryland USA
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44
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Lum KM, Sato Y, Beyer BA, Plaisted WC, Anglin JL, Lairson LL, Cravatt BF. Mapping Protein Targets of Bioactive Small Molecules Using Lipid-Based Chemical Proteomics. ACS Chem Biol 2017; 12:2671-2681. [PMID: 28930429 PMCID: PMC5650530 DOI: 10.1021/acschembio.7b00581] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Lipids play critical roles in cell biology, often through direct interactions with proteins. We recently described the use of photoreactive lipid probes combined with quantitative mass spectrometry to globally map lipid-protein interactions, and the effects of drugs on these interactions, in cells. Here, we investigate the broader potential of lipid-based chemical proteomic probes for determining the cellular targets of biologically active small molecules, including natural product derivatives and repurposed drugs of ill-defined mechanisms. We identify the prostaglandin-regulatory enzyme PTGR2 as a target of the antidiabetic hops derivative KDT501 and show that miconazole-an antifungal drug that attenuates disease severity in preclinical models of multiple sclerosis-inhibits SGPL1, an enzyme that degrades the signaling lipid sphingosine-1-phosphate, drug analogues of which are used to treat multiple sclerosis in humans. Our findings highlight the versatility of lipid-based chemical proteomics probes for mapping small molecule-protein interactions in human cells to gain mechanistic understanding of bioactive compounds.
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Affiliation(s)
- Kenneth M. Lum
- Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Yoshiaki Sato
- Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Brittney A. Beyer
- Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | | | - Justin L. Anglin
- California Institute for Biomedical Research, La Jolla, CA 92037, USA
| | - Luke L. Lairson
- Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Benjamin F. Cravatt
- Department of Molecular Medicine, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
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45
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Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics 2017; 14:859-873. [PMID: 28812220 PMCID: PMC5722770 DOI: 10.1007/s13311-017-0565-4] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.
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Affiliation(s)
- Burhan Z Chaudhry
- Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue/U10, Cleveland, OH, 44195, USA.
| | - Jeffrey A Cohen
- Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue/U10, Cleveland, OH, 44195, USA
| | - Devon S Conway
- Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue/U10, Cleveland, OH, 44195, USA
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46
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Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease. Sci Rep 2017; 7:5280. [PMID: 28706199 PMCID: PMC5509685 DOI: 10.1038/s41598-017-05709-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 06/01/2017] [Indexed: 12/22/2022] Open
Abstract
Huntington’s disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.
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47
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Guo XZJ, Thomas PG. New fronts emerge in the influenza cytokine storm. Semin Immunopathol 2017; 39:541-550. [PMID: 28555383 PMCID: PMC5580809 DOI: 10.1007/s00281-017-0636-y] [Citation(s) in RCA: 205] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 04/23/2017] [Indexed: 12/17/2022]
Abstract
Influenza virus is a significant pathogen in humans and animals with the ability to cause extensive morbidity and mortality. Exuberant immune responses induced following infection have been described as a "cytokine storm," associated with excessive levels of proinflammatory cytokines and widespread tissue damage. Recent studies have painted a more complex picture of cytokine networks and their contributions to clinical outcomes. While many cytokines clearly inflict immunopathology, others have non-pathological delimited roles in sending alarm signals, facilitating viral clearance, and promoting tissue repair, such as the IL-33-amphiregulin axis, which plays a key role in resolving some types of lung damage. Recent literature suggests that type 2 cytokines, traditionally thought of as not involved in anti-influenza immunity, may play an important regulatory role. Here, we discuss the diverse roles played by cytokines after influenza infection and highlight new, serene features of the cytokine storm, while highlighting the specific functions of relevant cytokines that perform unique immune functions and may have applications for influenza therapy.
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Affiliation(s)
- Xi-Zhi J Guo
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA
- Integrated Biomedical Sciences Program, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
- Integrated Biomedical Sciences Program, Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
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48
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Vijayan M, Xia C, Song YE, Ngo H, Studstill CJ, Drews K, Fox TE, Johnson MC, Hiscott J, Kester M, Alexander S, Hahm B. Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection. THE JOURNAL OF IMMUNOLOGY 2017; 199:677-687. [PMID: 28600291 DOI: 10.4049/jimmunol.1601959] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 05/12/2017] [Indexed: 12/28/2022]
Abstract
Sphingosine 1-phosphate (S1P) lyase (SPL) is an intracellular enzyme that mediates the irreversible degradation of the bioactive lipid S1P. We have previously reported that overexpressed SPL displays anti-influenza viral activity; however, the underlying mechanism is incompletely understood. In this study, we demonstrate that SPL functions as a positive regulator of IKKε to propel type I IFN-mediated innate immune responses against viral infection. Exogenous SPL expression inhibited influenza A virus replication, which correlated with an increase in type I IFN production and IFN-stimulated gene accumulation upon infection. In contrast, the lack of SPL expression led to an elevated cellular susceptibility to influenza A virus infection. In support of this, SPL-deficient cells were defective in mounting an effective IFN response when stimulated by influenza viral RNAs. SPL augmented the activation status of IKKε and enhanced the kinase-induced phosphorylation of IRF3 and the synthesis of type I IFNs. However, the S1P degradation-incompetent form of SPL also enhanced IFN responses, suggesting that SPL's pro-IFN function is independent of S1P. Biochemical analyses revealed that SPL, as well as the mutant form of SPL, interacts with IKKε. Importantly, when endogenous IKKε was downregulated using a small interfering RNA approach, SPL's anti-influenza viral activity was markedly suppressed. This indicates that IKKε is crucial for SPL-mediated inhibition of influenza virus replication. Thus, the results illustrate the functional significance of the SPL-IKKε-IFN axis during host innate immunity against viral infection.
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Affiliation(s)
- Madhuvanthi Vijayan
- Department of Surgery, University of Missouri, Columbia, MO 65212.,Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
| | - Chuan Xia
- Department of Surgery, University of Missouri, Columbia, MO 65212.,Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
| | - Yul Eum Song
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
| | - Hanh Ngo
- Department of Surgery, University of Missouri, Columbia, MO 65212.,Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
| | - Caleb J Studstill
- Department of Surgery, University of Missouri, Columbia, MO 65212.,Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
| | - Kelly Drews
- Department of Pathology, University of Virginia, Charlottesville, VA 22908
| | - Todd E Fox
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22908
| | - Marc C Johnson
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
| | - John Hiscott
- Istituto Pasteur-Fondazione Cenci Bolognetti, 00161 Rome, Italy; and
| | - Mark Kester
- Department of Pharmacology, University of Virginia, Charlottesville, VA 22908
| | - Stephen Alexander
- Division of Biological Sciences, University of Missouri, Columbia, MO 65211
| | - Bumsuk Hahm
- Department of Surgery, University of Missouri, Columbia, MO 65212; .,Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212
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49
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Bustamante MF, Garcia-Carbonell R, Whisenant KD, Guma M. Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther 2017; 19:110. [PMID: 28569176 PMCID: PMC5452638 DOI: 10.1186/s13075-017-1303-3] [Citation(s) in RCA: 316] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
An increasing number of studies show how changes in intracellular metabolic pathways alter tumor and immune cell function. However, little information about metabolic changes in other cell types, including synovial fibroblasts, is available. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) are the most common cell type at the pannus–cartilage junction and contribute to joint destruction through their production of cytokines, chemokines, and matrix-degrading molecules and by migrating and invading joint cartilage. In this review, we show that these cells differ from healthy synovial fibroblasts, not only in their marker expression, proto-oncogene expression, or their epigenetic changes, but also in their intracellular metabolism. These metabolic changes must occur due to the stressful microenvironment of inflamed tissues, where concentrations of crucial nutrients such as glucose, glutamine, and oxygen are spatially and temporally heterogeneous. In addition, these metabolic changes will increase metabolite exchange between fibroblast and other synovial cells, which can potentially be activated. Glucose and phospholipid metabolism as well as bioactive lipids, including sphingosine-1-phosphate and lysophosphatidic acid, among others, are involved in FLS activation. These metabolic changes likely contribute to FLS involvement in aspects of immune response initiation or abnormal immune responses and strongly contribute to joint destruction.
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Affiliation(s)
- Marta F Bustamante
- Department of Medicine, School of Medicine, UCSD, 9500 Gilman Drive, La Jolla, CA, 92093-0663, USA
| | - Ricard Garcia-Carbonell
- Department of Medicine, School of Medicine, UCSD, 9500 Gilman Drive, La Jolla, CA, 92093-0663, USA
| | - Katrijn D Whisenant
- Department of Medicine, School of Medicine, UCSD, 9500 Gilman Drive, La Jolla, CA, 92093-0663, USA
| | - Monica Guma
- Department of Medicine, School of Medicine, UCSD, 9500 Gilman Drive, La Jolla, CA, 92093-0663, USA.
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50
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Dash RP, Rais R, Srinivas NR. Ponesimod, a selective sphingosine 1-phosphate (S1P 1) receptor modulator for autoimmune diseases: review of clinical pharmacokinetics and drug disposition. Xenobiotica 2017; 48:442-451. [PMID: 28489480 DOI: 10.1080/00498254.2017.1329568] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
1. Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator, is undergoing clinical development for the treatment of autoimmune diseases (multiple sclerosis/psoriasis). 2. Published literature data describing pharmacokinetic disposition of ponesimod were collected, reviewed and tabulated. 3. Across various clinical phase-I studies, ponesimod displayed consistent pharmacokinetics - relatively faster absorption peak time (approximately 2.5 h), elimination half-life of approximately 30 h and modest accumulation (2- to 2.6-fold). Ponesimod was extensively metabolized and two major metabolites were ACT-204426 and ACT-338375. 4. Extensive population pharmacokinetic-pharmacodynamic modeling has confirmed the therapeutic dose(s) for ponesimod to achieve the balance between safety (primarily heart rate) and efficacy using the maximum inhibition of the total lymphocytes as the pharmacodynamic marker. 5. None of the covariates (ethnicity, body weight, sex, diseased state including multiple sclerosis and psoriasis, food intake, formulation, etc.) examined in population pharmacokinetic model influenced the pharmacokinetics of ponesimod from a clinical relevance perspective. However, hepatic impairment (moderate/severe but not mild), profoundly influenced its disposition; and therefore, would necessitate dosage adjustment of ponesimod in clinical therapy. 6. Ponesimod has a favorable safety profile and pharmacokinetics, which will allow maximizing its ability to inhibit circulating lymphocytes in a given dosing regimen for treating autoimmune diseases.
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Affiliation(s)
- Ranjeet Prasad Dash
- a Drug Metabolism and Pharmacokinetics, Johns Hopkins Drug Discovery Program.,b Department of Neurology , Johns Hopkins University , Baltimore , MD , USA , and
| | - Rana Rais
- a Drug Metabolism and Pharmacokinetics, Johns Hopkins Drug Discovery Program.,b Department of Neurology , Johns Hopkins University , Baltimore , MD , USA , and
| | - Nuggehally R Srinivas
- c Drug Metabolism and Pharmacokinetics, Zydus Research Centre , Ahmedabad , Gujarat , India
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