|
1
|
Newton LS, Gathmann C, Ridewood S, Smith RJ, Wijaya AJ, Hornsby TW, Morling KL, Annett D, Chiozzi RZ, Reuschl AK, Govasli ML, Tan YY, Thorne LG, Jolly C, Thalassinos K, Ciulli A, Towers GJ, Selwood DL. Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV. Nat Commun 2025; 16:1484. [PMID: 39929804 PMCID: PMC11811207 DOI: 10.1038/s41467-025-56317-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Targeting host proteins that are crucial for viral replication offers a promising antiviral strategy. We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporine A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells and have high specificity for CypA confirmed by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA-targeting PROTACs inhibit viral replication potently and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.
Collapse
Affiliation(s)
- Lydia S Newton
- Division of Infection and Immunity, University College London, London, UK
| | - Clara Gathmann
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Sophie Ridewood
- Division of Infection and Immunity, University College London, London, UK
| | - Robert J Smith
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Andre J Wijaya
- Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK
| | - Thomas W Hornsby
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Kate L Morling
- Division of Infection and Immunity, University College London, London, UK
- Wolfson Institute for Biomedical Research, University College London, London, UK
| | - Dara Annett
- Division of Infection and Immunity, University College London, London, UK
| | - Riccardo Zenezini Chiozzi
- University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK
| | | | - Morten L Govasli
- Division of Infection and Immunity, University College London, London, UK
- Department of Biomedicine, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
| | - Ying Ying Tan
- Division of Infection and Immunity, University College London, London, UK
| | - Lucy G Thorne
- Division of Infection and Immunity, University College London, London, UK
- Department of Infectious Diseases, Imperial College London, London, UK
| | - Clare Jolly
- Division of Infection and Immunity, University College London, London, UK
| | - Konstantinos Thalassinos
- University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK
- Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK
| | - Alessio Ciulli
- Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK
| | - Greg J Towers
- Division of Infection and Immunity, University College London, London, UK.
| | - David L Selwood
- Wolfson Institute for Biomedical Research, University College London, London, UK.
| |
Collapse
|
|
2
|
Jin S, Zhang M, Qiao X. Cyclophilin A: promising target in cancer therapy. Cancer Biol Ther 2024; 25:2425127. [PMID: 39513594 PMCID: PMC11552246 DOI: 10.1080/15384047.2024.2425127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/08/2024] [Accepted: 10/30/2024] [Indexed: 11/15/2024] Open
Abstract
Cyclophilin A (CypA), a member of the immunophilin family, stands out as the most prevalent among the cyclophilins found in humans. Beyond serving as the intracellular receptor for the immunosuppressive drug cyclosporine A (CsA), CypA exerts critical functions within the cell via its peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is crucial for processes, such as protein folding, trafficking, assembly, modulation of immune responses, and cell signaling. Increasing evidence indicates that CypA is up-regulated in a variety of human cancers and it may be a novel potential therapeutic target for cancer treatment. Therefore, gaining a thorough understanding of CypA's contribution to cancer could yield fresh perspectives and inform the development of innovative therapeutic approaches. This review delves into the multifaceted roles of CypA in cancer biology and explores the therapeutic potential of targeting CypA.
Collapse
Affiliation(s)
- Shujuan Jin
- Shenzhen Institute for Technology Innovation, National Institute of Metrology, Shenzhen, Guangdong, China
| | - Mengjiao Zhang
- Chenxi Women’s and Children’s Hospital, Huaihua, Hunan, China
| | - Xiaoting Qiao
- Shenzhen Institute for Technology Innovation, National Institute of Metrology, Shenzhen, Guangdong, China
| |
Collapse
|
|
3
|
Stauffer WT, Goodman AZ, Gallay PA. Cyclophilin inhibition as a strategy for the treatment of human disease. Front Pharmacol 2024; 15:1417945. [PMID: 39045055 PMCID: PMC11264201 DOI: 10.3389/fphar.2024.1417945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 06/14/2024] [Indexed: 07/25/2024] Open
Abstract
Cyclophilins (Cyps), characterized as peptidyl-prolyl cis-trans isomerases (PPIases), are highly conserved and ubiquitous, playing a crucial role in protein folding and cellular signaling. This review summarizes the biochemical pathways mediated by Cyps, including their involvement in pathological states such as viral replication, inflammation, and cancer progression, to underscore the therapeutic potential of Cyp inhibition. The exploration of Cyp inhibitors (CypI) in this review, particularly non-immunosuppressive cyclosporine A (CsA) derivatives, highlights their significance as therapeutic agents. The structural and functional nuances of CsA derivatives are examined, including their efficacy, mechanism of action, and the balance between therapeutic benefits and off-target effects. The landscape of CypI is evaluated to emphasize the clinical need for targeted approaches to exploit the complex biology of Cyps and to propose future directions for research that may enhance the utility of non-immunosuppressive CsA derivatives in treating diseases where Cyps play a key pathological role.
Collapse
Affiliation(s)
| | | | - Philippe A. Gallay
- Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla, CA, United States
| |
Collapse
|
|
4
|
Coluccino G, Muraca VP, Corazza A, Lippe G. Cyclophilin D in Mitochondrial Dysfunction: A Key Player in Neurodegeneration? Biomolecules 2023; 13:1265. [PMID: 37627330 PMCID: PMC10452829 DOI: 10.3390/biom13081265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/11/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the "powerhouse of the cell" turns into the "factory of death" is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction with its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer's Disease and Parkinson's Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders.
Collapse
Affiliation(s)
- Gabriele Coluccino
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (V.P.M.); (A.C.)
| | | | | | - Giovanna Lippe
- Department of Medicine (DAME), University of Udine, 33100 Udine, Italy; (V.P.M.); (A.C.)
| |
Collapse
|
|
5
|
Gurung D, Danielson JA, Tasnim A, Zhang JT, Zou Y, Liu JY. Proline Isomerization: From the Chemistry and Biology to Therapeutic Opportunities. BIOLOGY 2023; 12:1008. [PMID: 37508437 PMCID: PMC10376262 DOI: 10.3390/biology12071008] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/27/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
Proline isomerization, the process of interconversion between the cis- and trans-forms of proline, is an important and unique post-translational modification that can affect protein folding and conformations, and ultimately regulate protein functions and biological pathways. Although impactful, the importance and prevalence of proline isomerization as a regulation mechanism in biological systems have not been fully understood or recognized. Aiming to fill gaps and bring new awareness, we attempt to provide a wholistic review on proline isomerization that firstly covers what proline isomerization is and the basic chemistry behind it. In this section, we vividly show that the cause of the unique ability of proline to adopt both cis- and trans-conformations in significant abundance is rooted from the steric hindrance of these two forms being similar, which is different from that in linear residues. We then discuss how proline isomerization was discovered historically followed by an introduction to all three types of proline isomerases and how proline isomerization plays a role in various cellular responses, such as cell cycle regulation, DNA damage repair, T-cell activation, and ion channel gating. We then explore various human diseases that have been linked to the dysregulation of proline isomerization. Finally, we wrap up with the current stage of various inhibitors developed to target proline isomerases as a strategy for therapeutic development.
Collapse
Affiliation(s)
- Deepti Gurung
- Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614, USA
- Department of Cell and Cancer Biology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Jacob A Danielson
- Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Afsara Tasnim
- Department of Bioengineering, University of Toledo College of Engineering, Toledo, OH 43606, USA
| | - Jian-Ting Zhang
- Department of Cell and Cancer Biology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Yue Zou
- Department of Cell and Cancer Biology, University of Toledo College of Medicine, Toledo, OH 43614, USA
| | - Jing-Yuan Liu
- Department of Medicine, University of Toledo College of Medicine, Toledo, OH 43614, USA
- Department of Cell and Cancer Biology, University of Toledo College of Medicine, Toledo, OH 43614, USA
- Department of Bioengineering, University of Toledo College of Engineering, Toledo, OH 43606, USA
| |
Collapse
|
|
6
|
Li J, Xue Y, Wang X, Smith LS, He B, Liu S, Zhu H. Tissue- and cell-expression of druggable host proteins provide insights into repurposing drugs for COVID-19. Clin Transl Sci 2022; 15:2796-2811. [PMID: 36259251 PMCID: PMC9747131 DOI: 10.1111/cts.13400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 08/18/2022] [Accepted: 08/23/2022] [Indexed: 01/26/2023] Open
Abstract
Several human host proteins play important roles in the lifecycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Many drugs targeting these host proteins have been investigated as potential therapeutics for coronavirus disease 2019 (COVID-19). The tissue-specific expressions of selected host proteins were summarized using proteomics data retrieved from the Human Protein Atlas, ProteomicsDB, Human Proteome Map databases, and a clinical COVID-19 study. Protein expression features in different cell lines were summarized based on recent proteomics studies. The half-maximal effective concentration or half-maximal inhibitory concentration values were collected from in vitro studies. The pharmacokinetic data were mainly from studies in healthy subjects or non-COVID-19 patients. Considerable tissue-specific expression patterns were observed for several host proteins. ACE2 expression in the lungs was significantly lower than in many other tissues (e.g., the kidneys and intestines); TMPRSS2 expression in the lungs was significantly lower than in other tissues (e.g., the prostate and intestines). The expression levels of endocytosis-associated proteins CTSL, CLTC, NPC1, and PIKfyve in the lungs were comparable to or higher than most other tissues. TMPRSS2 expression was markedly different between cell lines, which could be associated with the cell-dependent antiviral activities of several drugs. Drug delivery receptor ICAM1 and CTSB were expressed at a higher level in the lungs than in other tissues. In conclusion, the cell- and tissue-specific proteomics data could help interpret the in vitro antiviral activities of host-directed drugs in various cells and aid the transition of the in vitro findings to clinical research to develop safe and effective therapeutics for COVID-19.
Collapse
Affiliation(s)
- Jiapeng Li
- Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborMichiganUSA
| | - Yanling Xue
- Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborMichiganUSA
| | - Xinwen Wang
- Department of Pharmaceutical SciencesNortheast Ohio Medical University College of PharmacyRootstownOhioUSA
| | - Logan S. Smith
- Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborMichiganUSA
| | - Bing He
- Department of Computational Medicine and BioinformaticsUniversity of MichiganAnn ArborMichiganUSA
| | - Shuhan Liu
- Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborMichiganUSA
| | - Hao‐Jie Zhu
- Department of Clinical PharmacyUniversity of Michigan College of PharmacyAnn ArborMichiganUSA
| |
Collapse
|
|
7
|
Schiene‐Fischer C, Fischer G, Braun M. Non-Immunosuppressive Cyclophilin Inhibitors. Angew Chem Int Ed Engl 2022; 61:e202201597. [PMID: 35290695 PMCID: PMC9804594 DOI: 10.1002/anie.202201597] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Indexed: 01/05/2023]
Abstract
Cyclophilins, enzymes with peptidyl-prolyl cis/trans isomerase activity, are relevant to a large variety of biological processes. The most abundant member of this enzyme family, cyclophilin A, is the cellular receptor of the immunosuppressive drug cyclosporine A (CsA). As a consequence of the pathophysiological role of cyclophilins, particularly in viral infections, there is a broad interest in cyclophilin inhibition devoid of immunosuppressive activity. This Review first gives an introduction into the physiological and pathophysiological roles of cyclophilins. The presentation of non-immunosuppressive cyclophilin inhibitors will commence with drugs based on chemical modifications of CsA. The naturally occurring macrocyclic sanglifehrins have become other lead structures for cyclophilin-inhibiting drugs. Finally, de novo designed compounds, whose structures are not derived from or inspired by natural products, will be presented. Relevant synthetic concepts will be discussed, but the focus will also be on biochemical studies, structure-activity relationships, and clinical studies.
Collapse
Affiliation(s)
- Cordelia Schiene‐Fischer
- Institute of Biochemistry and BiotechnologyMartin-Luther-University Halle-Wittenberg06099Halle (Saale)Germany
| | - Gunter Fischer
- Max Planck Institute for Biophysical Chemistry37077GöttingenGermany
| | - Manfred Braun
- Institute of Organic and Macromolecular ChemistryHeinrich-Heine-University Düsseldorf40225DüsseldorfGermany
| |
Collapse
|
|
8
|
Han J, Kyu Lee M, Jang Y, Cho WJ, Kim M. Repurposing of cyclophilin A inhibitors as broad-spectrum antiviral agents. Drug Discov Today 2022; 27:1895-1912. [PMID: 35609743 PMCID: PMC9123807 DOI: 10.1016/j.drudis.2022.05.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 03/30/2022] [Accepted: 05/18/2022] [Indexed: 12/28/2022]
Abstract
Cyclophilin A (CypA) is linked to diverse human diseases including viral infections. With the worldwide emergence of severe acute respiratory coronavirus 2 (SARS-CoV-2), drug repurposing has been highlighted as a strategy with the potential to speed up antiviral development. Because CypA acts as a proviral component in hepatitis C virus, coronavirus and HIV, its inhibitors have been suggested as potential treatments for these infections. Here, we review the structure of cyclosporin A and sanglifehrin A analogs as well as synthetic micromolecules inhibiting CypA; and we discuss their broad-spectrum antiviral efficacy in the context of the virus lifecycle.
Collapse
Affiliation(s)
- Jinhe Han
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Myoung Kyu Lee
- Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea
| | - Yejin Jang
- Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea
| | - Won-Jea Cho
- College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea.
| | - Meeheyin Kim
- Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea.
| |
Collapse
|
|
9
|
Braun M, Schiene-Fischer C, Fischer G. Non‐Immunosuppressive Cyclophilin Inhibitors. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202201597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Manfred Braun
- Heinrich-Heine-Universität Düsseldorf: Heinrich-Heine-Universitat Dusseldorf Organic CHemistry Universitätsstr. 1 40225 Düsseldorf GERMANY
| | - Cordelia Schiene-Fischer
- Martin-Luther-Universität Halle-Wittenberg: Martin-Luther-Universitat Halle-Wittenberg Institute of Biochemistry and Biotechnology, GERMANY
| | - Gunter Fischer
- Max-Planck-Institut für Biophysikalische Chemie Abteilung Meiosis: Max-Planck-Institut fur Multidisziplinare Naturwissenschaften Abteilung Meiosis Max Planck Institute for Biophysical Chemistry GERMANY
| |
Collapse
|
|
10
|
Devaux CA, Melenotte C, Piercecchi-Marti MD, Delteil C, Raoult D. Cyclosporin A: A Repurposable Drug in the Treatment of COVID-19? Front Med (Lausanne) 2021; 8:663708. [PMID: 34552938 PMCID: PMC8450353 DOI: 10.3389/fmed.2021.663708] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 08/04/2021] [Indexed: 12/22/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is now at the forefront of major health challenge faced globally, creating an urgent need for safe and efficient therapeutic strategies. Given the high attrition rates, high costs, and quite slow development of drug discovery, repurposing of known FDA-approved molecules is increasingly becoming an attractive issue in order to quickly find molecules capable of preventing and/or curing COVID-19 patients. Cyclosporin A (CsA), a common anti-rejection drug widely used in transplantation, has recently been shown to exhibit substantial anti-SARS-CoV-2 antiviral activity and anti-COVID-19 effect. Here, we review the molecular mechanisms of action of CsA in order to highlight why this molecule seems to be an interesting candidate for the therapeutic management of COVID-19 patients. We conclude that CsA could have at least three major targets in COVID-19 patients: (i) an anti-inflammatory effect reducing the production of proinflammatory cytokines, (ii) an antiviral effect preventing the formation of the viral RNA synthesis complex, and (iii) an effect on tissue damage and thrombosis by acting against the deleterious action of angiotensin II. Several preliminary CsA clinical trials performed on COVID-19 patients report lower incidence of death and suggest that this strategy should be investigated further in order to assess in which context the benefit/risk ratio of repurposing CsA as first-line therapy in COVID-19 is the most favorable.
Collapse
Affiliation(s)
- Christian A. Devaux
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
- CNRS, Marseille, France
| | - Cléa Melenotte
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Marie-Dominique Piercecchi-Marti
- Department of Legal Medicine, Hôpital de la Timone, Marseille University Hospital Center, Marseille, France
- Aix Marseille Univ, CNRS, EFS, ADES, Marseille, France
| | - Clémence Delteil
- Department of Legal Medicine, Hôpital de la Timone, Marseille University Hospital Center, Marseille, France
- Aix Marseille Univ, CNRS, EFS, ADES, Marseille, France
| | - Didier Raoult
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| |
Collapse
|
|
11
|
Pawlotsky JM. COVID-19 Pandemic: Time to Revive the Cyclophilin Inhibitor Alisporivir. Clin Infect Dis 2020; 71:2191-2194. [PMID: 32409832 PMCID: PMC7239253 DOI: 10.1093/cid/ciaa587] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
December 2019 saw the emergence of a new epidemic of pneumonia of varying severity, called COVID-19, caused by a newly identified coronavirus, SARS-CoV-2. No therapeutic option is available to treat this infection that has already killed more than 235,000 people worldwide. This Viewpoint summarizes the strong scientific arguments supporting the use of alisporivir, a non-immunosuppressive analogue of cyclosporine A with potent cyclophilin inhibition properties that has reached Phase 3 clinical development, for the treatment of COVID-19. They include the strong cyclophilin dependency of the lifecycle of many coronaviruses, including SARS-CoV and MERS-CoV, and preclinical data showing strong antiviral and cytoprotective properties of alisporivir in various models of coronavirus infection, including SARS-CoV-2. Alisporivir should be tested without delay on both virological and clinical endpoints in patients with or at-risk of severe forms of SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Jean-Michel Pawlotsky
- Department of Virology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, Créteil, France.,Inserm U955, Créteil, France
| |
Collapse
|
|
12
|
Poulsen NN, von Brunn A, Hornum M, Blomberg Jensen M. Cyclosporine and COVID-19: Risk or favorable? Am J Transplant 2020; 20:2975-2982. [PMID: 32777170 PMCID: PMC7436557 DOI: 10.1111/ajt.16250] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/06/2020] [Accepted: 07/27/2020] [Indexed: 01/25/2023]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is declared a global health emergency. COVID-19 is triggered by a novel coronavirus: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Baseline characteristics of admitted patients with COVID-19 show that adiposity, diabetes, and hypertension are risk factors for developing severe disease, but so far immunosuppressed patients who are listed as high-risk patients have not been more susceptible to severe COVID-19 than the rest of the population. Multiple clinical trials are currently being conducted, which may identify more drugs that can lower mortality, morbidity, and burden on the society. Several independent studies have convincingly shown that cyclosporine inhibit replication of several different coronaviruses in vitro. The cyclosporine-analog alisporivir has recently been shown to inhibit SARS-CoV-2 in vitro. These findings are intriguing, although there is no clinical evidence for a protective effect to reduce the likelihood of severe COVID-19 or to treat the immune storm or acute respiratory distress syndrome (ARDS) that often causes severe morbidity. Here, we review the putative link between COVID-19 and cyclosporine, while we await more robust clinical data.
Collapse
Affiliation(s)
- Nadia Nicholine Poulsen
- Department of Growth and Reproduction, Group of Skeletal, Mineral, and Gonadal Endocrinology, Rigshospitalet, Copenhagen, Denmark
| | - Albrecht von Brunn
- Max von Pettenkofer-Institute, Ludwig-Maximilians-University Munich/German Center for Infection Research (DZIF), Munich, Germany
| | - Mads Hornum
- Department of Nephrology, Rigshospitalet, Copenhagen, Denmark,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Martin Blomberg Jensen
- Department of Growth and Reproduction, Group of Skeletal, Mineral, and Gonadal Endocrinology, Rigshospitalet, Copenhagen, Denmark,Division of Bone and Mineral Research, HSDM/HMS Harvard University, Boston, MA, USA,Correspondence Martin Blomberg Jensen
| |
Collapse
|
|
13
|
Talele TT. Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon. J Med Chem 2020; 63:13291-13315. [PMID: 32805118 DOI: 10.1021/acs.jmedchem.0c00829] [Citation(s) in RCA: 196] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A quaternary carbon bears four other carbon substituents or combination of four non-hydrogen substituents at four vertices of a tetrahedron. The spirocyclic quaternary carbon positioned at the center of a bioactive molecule offers conformational rigidity, which in turn reduces the penalty for conformational entropy. The quaternary carbon is a predominant feature of natural product structures and has been associated with more effective and selective binding to target proteins compared to planar compounds with a high sp2 count. The presence of a quaternary carbon stereocenter allows the exploration of novel chemical space to obtain new molecules with enhanced three-dimensionality. These characteristics, coupled to an increasing awareness to develop sp3-rich molecules, boosted utility of quaternary carbon stereocenters in bioactive compounds. It is hoped that this Perspective will inspire the chemist to utilize quaternary carbon stereocenters to enhance potency, selectivity, and other drug-like properties.
Collapse
Affiliation(s)
- Tanaji T Talele
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States
| |
Collapse
|
|
14
|
Abstract
Over a long period of time, humans have explored many natural resources looking for remedies of various ailments. Traditional medicines have played an intrinsic role in human life for thousands of years, with people depending on medicinal plants and their products as dietary supplements as well as using them therapeutically for treatment of chronic disorders, such as cancer, malaria, diabetes, arthritis, inflammation, and liver and cardiac disorders. However, plant resources are not sufficient for treatment of recently emerging diseases. In addition, the seasonal availability and other political factors put constrains on some rare plant species. The actual breakthrough in drug discovery came concurrently with the discovery of penicillin from Penicillium notatum in 1929. This discovery dramatically changed the research of natural products and positioned microbial natural products as one of the most important clues in drug discovery due to availability, variability, great biodiversity, unique structures, and the bioactivities produced. The number of commercially available therapeutically active compounds from microbial sources to date exceeds those discovered from other sources. In this review, we introduce a short history of microbial drug discovery as well as certain features and recent research approaches, specifying the microbial origin, their featured molecules, and the diversity of the producing species. Moreover, we discuss some bioactivities as well as new approaches and trends in research in this field.
Collapse
|
|
15
|
Lindblom RSJ, Higgins GC, Nguyen TV, Arnstein M, Henstridge DC, Granata C, Snelson M, Thallas-Bonke V, Cooper ME, Forbes JM, Coughlan MT. Delineating a role for the mitochondrial permeability transition pore in diabetic kidney disease by targeting cyclophilin D. Clin Sci (Lond) 2020; 134:239-259. [PMID: 31943002 DOI: 10.1042/cs20190787] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 01/10/2020] [Accepted: 01/16/2020] [Indexed: 12/13/2022]
Abstract
Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif-/-) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif-/- mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif-/- as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.
Collapse
Affiliation(s)
- Runa S J Lindblom
- Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | - Gavin C Higgins
- Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
- Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Tuong-Vi Nguyen
- Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| | - Maryann Arnstein
- Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | | | - Cesare Granata
- Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | - Matthew Snelson
- Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | | | - Mark E Cooper
- Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | - Josephine M Forbes
- Glycation and Diabetes Group, Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Central Clinical School, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
- Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
| |
Collapse
|
|
16
|
Mei F, Tu Y. Cyclophilin B enhances the proliferation and differentiation of MC3T3-E1 cells via JAK2/STAT3 signaling pathway. BIOTECHNOL BIOTEC EQ 2019. [DOI: 10.1080/13102818.2019.1684842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Fan Mei
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, PR China
| | - Yanhong Tu
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, PR China
| |
Collapse
|
|
17
|
García-Serradilla M, Risco C, Pacheco B. Drug repurposing for new, efficient, broad spectrum antivirals. Virus Res 2019; 264:22-31. [PMID: 30794895 PMCID: PMC7114681 DOI: 10.1016/j.virusres.2019.02.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 02/18/2019] [Accepted: 02/18/2019] [Indexed: 12/26/2022]
Abstract
Emerging viruses are a major threat to human health. Recent outbreaks have emphasized the urgent need for new antiviral treatments. For several pathogenic viruses, considerable efforts have focused on vaccine development. However, during epidemics infected individuals need to be treated urgently. High-throughput screening of clinically tested compounds provides a rapid means to identify undiscovered, antiviral functions for well-characterized therapeutics. Repurposed drugs can bypass part of the early cost and time needed for validation and authorization. In this review we describe recent efforts to find broad spectrum antivirals through drug repurposing. We have chosen several candidates and propose strategies to understand their mechanism of action and to determine how resistance to antivirals develops in infected cells.
Collapse
Affiliation(s)
- Moisés García-Serradilla
- Cell Structure Laboratory, National Center for Biotechnology, National Research Council, CNB-CSIC, Darwin 3, UAM, campus de Cantoblanco, 28049 Madrid, Spain
| | - Cristina Risco
- Cell Structure Laboratory, National Center for Biotechnology, National Research Council, CNB-CSIC, Darwin 3, UAM, campus de Cantoblanco, 28049 Madrid, Spain.
| | - Beatriz Pacheco
- Cell Structure Laboratory, National Center for Biotechnology, National Research Council, CNB-CSIC, Darwin 3, UAM, campus de Cantoblanco, 28049 Madrid, Spain.
| |
Collapse
|
|
18
|
Stanciu C, Trifan A, Muzica C, Sfarti C. Efficacy and safety of alisporivir for the treatment of hepatitis C infection. Expert Opin Pharmacother 2019; 20:379-384. [PMID: 30576256 DOI: 10.1080/14656566.2018.1560424] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023]
Abstract
Alisporivir (ALV) (previously known as Debio 025) is a potent, pangenotypic host-targeting antiviral oral agent acting on cyclophilin A, which is necessary for HCV replication. Areas covered: This article reviews the therapeutic efficacy and safety of ALV for the treatment of HCV infection. Expert opinion: Direct-acting antivirals (DAAs) have revolutionized the HCV antiviral treatment paradigm with success rates well above 95% for all HCV genotypes. However, challenges still remain in certain patient populations such as those who have developed resistance and have experienced multi-DAA failure. To cure HCV infection, a treatment regimen must combine antiviral potency and a high barrier to resistance. ALV fulfills this need as shown by the studies evaluating its clinical efficacy. Nevertheless, ALV missed the chance to be included in the HCV treatment armamentarium after the FDA halted clinical studies following reports of serious side effects (three cases of pancreatitis, one lethal). However, it is possible that ALV could still be considered for HCV-infected non-cirrhotic patients that are infected with a multiresistant virus or with HCV genotype 3, although it must be said that the drug industry would be reluctant to invest in new antivirals if the current clinical need is effectively met.
Collapse
Affiliation(s)
- Carol Stanciu
- a Department of Gastroenterology , Grigore T. Popa University of Medicine and Pharmacy , Iasi , Romania
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
| | - Anca Trifan
- a Department of Gastroenterology , Grigore T. Popa University of Medicine and Pharmacy , Iasi , Romania
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
| | - Cristina Muzica
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
| | - Catalin Sfarti
- a Department of Gastroenterology , Grigore T. Popa University of Medicine and Pharmacy , Iasi , Romania
- b Department of Gastroenterology , St. Spiridon, Emergency Clinical Hospital , Iasi , Romania
| |
Collapse
|
|
19
|
Ashraf MU, Iman K, Khalid MF, Salman HM, Shafi T, Rafi M, Javaid N, Hussain R, Ahmad F, Shahzad-Ul-Hussan S, Mirza S, Shafiq M, Afzal S, Hamera S, Anwar S, Qazi R, Idrees M, Qureshi SA, Chaudhary SU. Evolution of efficacious pangenotypic hepatitis C virus therapies. Med Res Rev 2018; 39:1091-1136. [PMID: 30506705 DOI: 10.1002/med.21554] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 10/11/2018] [Accepted: 10/11/2018] [Indexed: 12/12/2022]
Abstract
Hepatitis C compromises the quality of life of more than 350 million individuals worldwide. Over the last decade, therapeutic regimens for treating hepatitis C virus (HCV) infections have undergone rapid advancements. Initially, structure-based drug design was used to develop molecules that inhibit viral enzymes. Subsequently, establishment of cell-based replicon systems enabled investigations into various stages of HCV life cycle including its entry, replication, translation, and assembly, as well as role of host proteins. Collectively, these approaches have facilitated identification of important molecules that are deemed essential for HCV life cycle. The expanded set of putative virus and host-encoded targets has brought us one step closer to developing robust strategies for efficacious, pangenotypic, and well-tolerated medicines against HCV. Herein, we provide an overview of the development of various classes of virus and host-directed therapies that are currently in use along with others that are undergoing clinical evaluation.
Collapse
Affiliation(s)
- Muhammad Usman Ashraf
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Kanzal Iman
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Muhammad Farhan Khalid
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Department of Biomedical Engineering, University of Engineering and Technology, Lahore, Pakistan
| | - Hafiz Muhammad Salman
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan.,Plant Biotechnology Laboratory, Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan
| | - Talha Shafi
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Momal Rafi
- Department of Statistics, University of Gujrat, Gujrat, Pakistan
| | - Nida Javaid
- Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Rashid Hussain
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Fayyaz Ahmad
- Department of Statistics, University of Gujrat, Gujrat, Pakistan
| | | | - Shaper Mirza
- Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| | - Muhammad Shafiq
- Plant Biotechnology Laboratory, Institute of Agricultural Sciences, University of the Punjab, Lahore, Pakistan
| | - Samia Afzal
- Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Sadia Hamera
- Department of Plant Genetics, Institute of Life Sciences, University of Rostock, Germany
| | - Saima Anwar
- Department of Biomedical Engineering, University of Engineering and Technology, Lahore, Pakistan
| | - Romena Qazi
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan
| | - Muhammad Idrees
- Virology Laboratory, Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.,Hazara University, Mansehra, Pakistan
| | - Sohail A Qureshi
- Institute of Integrative Biosciences, CECOS-University of Information Technology and Emerging Sciences, Peshawar, Pakistan
| | - Safee Ullah Chaudhary
- Biomedical Informatics Research Laboratory, Department of Biology, Lahore University of Management Sciences, Lahore, Pakistan
| |
Collapse
|
|
20
|
Dujardin M, Bouckaert J, Rucktooa P, Hanoulle X. X-ray structure of alisporivir in complex with cyclophilin A at 1.5 Å resolution. Acta Crystallogr F Struct Biol Commun 2018; 74:583-592. [PMID: 30198892 PMCID: PMC6130424 DOI: 10.1107/s2053230x18010415] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 07/18/2018] [Indexed: 12/14/2022] Open
Abstract
Alisporivir (ALV) is an 11-amino-acid hydrophobic cyclic peptide with N-methyl-D-alanine and N-ethyl-L-valine (NEV) residues at positions 3 and 4, respectively. ALV is a non-immunosuppressive cyclosporin A (CsA) derivative. This inhibitor targets cyclophilins (Cyps), a family of proteins with peptidyl-prolyl cis/trans isomerase enzymatic activity. Cyps act as protein chaperones and are involved in numerous cellular functions. Moreover, Cyps have been shown to be an essential cofactor for the replication of many viruses, including Hepatitis C virus and Human immunodeficiency virus, and have also been shown to be involved in mitochondrial diseases. For these reasons, cyclophilins represent an attractive drug target. The structure of ALV in complex with cyclophilin A (CypA), the most abundant Cyp in humans, has been determined at 1.5 Å resolution. This first structure of the CypA-ALV complex shows that the binding of ALV is highly similar to that of CsA. The high resolution allowed the unambiguous determination of the conformations of residues 3 and 4 in ALV when bound to its target. In particular, the side-chain conformation of NEV4 precludes the interaction of the CypA-ALV complex with calcineurin, a cellular protein phosphatase involved in the immune response, which explains the non-immunosuppressive property of ALV. This study provides detailed molecular insights into the CypA-ALV interaction.
Collapse
Affiliation(s)
- Marie Dujardin
- UGSF–UMR8576, University of Lille, CNRS, F-59000 Lille, France
| | - Julie Bouckaert
- UGSF–UMR8576, University of Lille, CNRS, F-59000 Lille, France
| | | | - Xavier Hanoulle
- UGSF–UMR8576, University of Lille, CNRS, F-59000 Lille, France
| |
Collapse
|
|
21
|
Mackman RL, Steadman VA, Dean DK, Jansa P, Poullennec KG, Appleby T, Austin C, Blakemore CA, Cai R, Cannizzaro C, Chin G, Chiva JYC, Dunbar NA, Fliri H, Highton AJ, Hui H, Ji M, Jin H, Karki K, Keats AJ, Lazarides L, Lee YJ, Liclican A, Mish M, Murray B, Pettit SB, Pyun P, Sangi M, Santos R, Sanvoisin J, Schmitz U, Schrier A, Siegel D, Sperandio D, Stepan G, Tian Y, Watt GM, Yang H, Schultz BE. Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle. J Med Chem 2018; 61:9473-9499. [PMID: 30074795 DOI: 10.1021/acs.jmedchem.8b00802] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
Collapse
Affiliation(s)
- Richard L Mackman
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Victoria A Steadman
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - David K Dean
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Petr Jansa
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Karine G Poullennec
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Todd Appleby
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Carol Austin
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Caroline A Blakemore
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Ruby Cai
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Carina Cannizzaro
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Gregory Chin
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Jean-Yves C Chiva
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Neil A Dunbar
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Hans Fliri
- Cypralis Ltd. , Babraham Research Campus, Cambridge CB22 3AT , United Kingdom
| | - Adrian J Highton
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Hon Hui
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Mingzhe Ji
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Haolun Jin
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Kapil Karki
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Andrew J Keats
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Linos Lazarides
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Yu-Jen Lee
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Albert Liclican
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Michael Mish
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Bernard Murray
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Simon B Pettit
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Peter Pyun
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Michael Sangi
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Rex Santos
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Jonathan Sanvoisin
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Uli Schmitz
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Adam Schrier
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Dustin Siegel
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - David Sperandio
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - George Stepan
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Yang Tian
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Gregory M Watt
- Selcia Ltd. , Fyfield Business and Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom
| | - Hai Yang
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| | - Brian E Schultz
- Gilead Sciences Inc. , 333 Lakeside Drive , Foster City , California 94404 , United States
| |
Collapse
|
|
22
|
Garcia-Moreno M, Järvelin AI, Castello A. Unconventional RNA-binding proteins step into the virus-host battlefront. WILEY INTERDISCIPLINARY REVIEWS-RNA 2018; 9:e1498. [PMID: 30091184 PMCID: PMC7169762 DOI: 10.1002/wrna.1498] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/01/2018] [Accepted: 06/05/2018] [Indexed: 12/15/2022]
Abstract
The crucial participation of cellular RNA‐binding proteins (RBPs) in virtually all steps of virus infection has been known for decades. However, most of the studies characterizing this phenomenon have focused on well‐established RBPs harboring classical RNA‐binding domains (RBDs). Recent proteome‐wide approaches have greatly expanded the census of RBPs, discovering hundreds of proteins that interact with RNA through unconventional RBDs. These domains include protein–protein interaction platforms, enzymatic cores, and intrinsically disordered regions. Here, we compared the experimentally determined census of RBPs to gene ontology terms and literature, finding that 472 proteins have previous links with viruses. We discuss what these proteins are and what their roles in infection might be. We also review some of the pioneering examples of unorthodox RBPs whose RNA‐binding activity has been shown to be critical for virus infection. Finally, we highlight the potential of these proteins for host‐based therapies against viruses. This article is categorized under:
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
Collapse
Affiliation(s)
| | - Aino I Järvelin
- Department of Biochemistry, University of Oxford, Oxford, UK
| | | |
Collapse
|
|
23
|
Characterization of the Anti-Hepatitis C Virus Activity of New Nonpeptidic Small-Molecule Cyclophilin Inhibitors with the Potential for Broad Anti-Flaviviridae Activity. Antimicrob Agents Chemother 2018; 62:AAC.00126-18. [PMID: 29760125 PMCID: PMC6021681 DOI: 10.1128/aac.00126-18] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/19/2018] [Indexed: 12/17/2022] Open
Abstract
Although members of the Flaviviridae display high incidence, morbidity, and mortality rates, the development of specific antiviral drugs for each virus is unlikely. Cyclophilins, a family of host peptidyl-prolyl cis-trans isomerases (PPIases), play a pivotal role in the life cycles of many viruses and therefore represent an attractive target for broad-spectrum antiviral development. We report here the pangenotypic anti-hepatitis C virus (HCV) activity of a small-molecule cyclophilin inhibitor (SMCypI). Mechanistic and modeling studies revealed that the SMCypI bound to cyclophilin A in competition with cyclosporine (CsA), inhibited its PPIase activity, and disrupted the CypA-nonstructural protein 5A (NS5A) interaction. Resistance selection showed that the lead SMCypI hardly selected amino acid substitutions conferring low-level or no resistance in vitro. Interestingly, the SMCypI selected D320E and Y321H substitutions, located in domain II of the NS5A protein. These substitutions were previously associated with low-level resistance to cyclophilin inhibitors such as alisporivir. Finally, the SMCypI inhibited the replication of other members of the Flaviviridae family with higher 50% effective concentrations (EC50s) than for HCV. Thus, because of its chemical plasticity and simplicity of synthesis, our new family of SMCypIs represents a promising new class of drugs with the potential for broad-spectrum anti-Flaviviridae activity as well as an invaluable tool to explore the role of cyclophilins in viral life cycles.
Collapse
|
|
24
|
Crouchet E, Wrensch F, Schuster C, Zeisel MB, Baumert TF. Host-targeting therapies for hepatitis C virus infection: current developments and future applications. Therap Adv Gastroenterol 2018; 11:1756284818759483. [PMID: 29619090 PMCID: PMC5871046 DOI: 10.1177/1756284818759483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/15/2018] [Indexed: 02/04/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) worldwide. In the past few years, anti-HCV therapies have undergone a revolution with the approval of multiple direct-acting antivirals (DAAs), which enable interferon-free treatments with considerable improvement of sustained virologic response in patients. Today, DAAs have become the standard of care for HCV therapy. However, several limitations remain, which include access to therapy, treatment failure in a subset of patients and persistent risk of HCC development following cure in patients with advanced fibrosis. By targeting conserved host proteins involved in the HCV life cycle, host-targeting agents (HTAs) offer opportunities for pan-genotypic antiviral approaches with a high barrier to drug resistance. Moreover, when applied in combination with DAAs, HTAs could improve the management of difficult-to-treat patients by acting through a complementary mechanism of action. In this review, we summarize the different HTAs evaluated in preclinical and clinical development and discuss their potential role for anti-HCV therapies.
Collapse
Affiliation(s)
- Emilie Crouchet
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Florian Wrensch
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Catherine Schuster
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France
| | - Mirjam B. Zeisel
- Institut National de la Santé et de la Recherche Médicale (Inserm), U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France Université de Strasbourg, Strasbourg, France Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France
| | | |
Collapse
|
|
25
|
Zhao X, Xia C, Wang X, Wang H, Xin M, Yu L, Liang Y. Cyclophilin J PPIase Inhibitors Derived from 2,3-Quinoxaline-6 Amine Exhibit Antitumor Activity. Front Pharmacol 2018. [PMID: 29520233 PMCID: PMC5826973 DOI: 10.3389/fphar.2018.00126] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cyclophilin J (CyPJ), also called peptidylprolyl isomerase like 3, has been identified as a novel member of the cyclophilin family. Our previous research has resolved the three-dimensional structure of CyPJ and demonstrated the peptidylprolyl cis–trans isomerase (PPIase) activity of CyPJ, which can be inhibited by the common immunosuppressive drug cyclosporine A (CsA). Importantly, CyPJ is upregulated in hepatocellular carcinoma (HCC) and promotes tumor growth; CyPJ inhibition by CsA- or siRNA-based knockdown results in a remarkable suppression of HCC. These findings suggest that CyPJ may be a potential therapeutic target for HCC, and discovery of relevant inhibitors may facilitate development of a novel CyPJ-based targeting therapy. However, apart from the common inhibitor CsA, CyPJ has yet to be investigated as a target for cancer therapy. Here, we report structure-based identification of novel small molecule non-peptidic CyPJ inhibitors and their potential as antitumor lead compounds. Based on computer-aided virtual screening, in silico, and subsequently surface plasmon resonance analysis, 19 potential inhibitors of CyPJ were identified and selected for further evaluation of PPIase CyPJ inhibition in vitro. Thirteen out of 19 compounds exhibited notable inhibition against PPIase activity. Among them, the compound ZX-J-19, with a quinoxaline nucleus, showed potential for tumor inhibition; thus, we selected it for further structure–activity optimization. A total of 22 chemical derivatives with 2,3-substituted quinoxaline-6-amine modifications were designed and successfully synthesized. At least 2 out of the 22 derivatives, such as ZX-J-19j and ZX-J-19l, demonstrated remarkable inhibition of tumor cell growth, comparable to CsA but much stronger than 5-fluorouracil. These results indicate that these two small molecules represent novel potential lead compounds for CyPJ-based antitumor drug development.
Collapse
Affiliation(s)
- Xuemei Zhao
- College of Pharmacy, Taishan Medical University, Tai'an, China
| | - Chengcai Xia
- College of Pharmacy, Taishan Medical University, Tai'an, China
| | - Xiaodan Wang
- College of Pharmacy, Taishan Medical University, Tai'an, China
| | - Hao Wang
- College of Pharmacy, Taishan Medical University, Tai'an, China
| | - Ming Xin
- College of Pharmacy, Taishan Medical University, Tai'an, China
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
| | - Yulong Liang
- College of Pharmacy, Taishan Medical University, Tai'an, China.,Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, United States
| |
Collapse
|
|
26
|
Dyall J, Gross R, Kindrachuk J, Johnson RF, Olinger GG, Hensley LE, Frieman MB, Jahrling PB. Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies. Drugs 2017; 77:1935-1966. [PMID: 29143192 PMCID: PMC5733787 DOI: 10.1007/s40265-017-0830-1] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search was performed covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed. The main focus of the review is on drug development and the potential that drugs approved for other indications provide for repurposing. The drugs we discuss belong to a wide range of different drug classes, such as cancer therapeutics, antipsychotics, and antimalarials. In addition to their activity against MERS and SARS coronaviruses, many of these approved drugs have broad-spectrum potential and have already been in clinical use for treating other viral infections. A wealth of knowledge is available for these drugs. However, the information in this review is not meant to guide clinical decisions, and any therapeutic described here should only be used in context of a clinical trial. Potential targets for novel antivirals and antibodies are discussed as well as lessons learned from treatment development for other RNA viruses. The article concludes with a discussion of the gaps in our knowledge and areas for future research on emerging coronaviruses.
Collapse
Affiliation(s)
- Julie Dyall
- Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA.
| | - Robin Gross
- Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Jason Kindrachuk
- Department of Medical Microbiology, University of Manitoba, Winnipeg, MN, Canada
| | - Reed F Johnson
- Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | | | - Lisa E Hensley
- Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| | - Matthew B Frieman
- Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD, USA
| | - Peter B Jahrling
- Integrated Research Facility, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
- Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD, USA
| |
Collapse
|
|
27
|
Jin G, Lee J, Lee K. Chemical genetics-based development of small molecules targeting hepatitis C virus. Arch Pharm Res 2017; 40:1021-1036. [PMID: 28856597 DOI: 10.1007/s12272-017-0949-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 08/20/2017] [Indexed: 12/21/2022]
Abstract
Hepatitis C virus (HCV) infection is a major worldwide problem that has emerged as one of the most significant diseases affecting humans. There are currently no vaccines or efficient therapies without side effects, despite today's advanced medical technology. Currently, the common therapy for most patients (i.e. genotype 1) is combination of HCV-specific direct-acting antivirals (DAAs). Up to 2011, the standard of care (SOC) was a combination of peg-IFNα with ribavirin (RBV). After approval of NS3/4A protease inhibitor, SOC was peg-IFNα and RBV with either the first-generation DAAs boceprevir or telaprevir. In the past several years, various novel small molecules have been discovered and some of them (i.e., HCV polymerase, protease, helicase and entry inhibitors) have undergone clinical trials. Between 2013 and 2016, the second-generation DAA drugs simeprevir, asunaprevir, daclatasvir, dasabuvir, sofosbuvir, and elbasvir were approved, as well as the combinational drugs Harvoni®, Zepatier®, Technivie®, and Epclusa®. A number of reviews have been recently published describing the structure-activity relationship (SAR) in the development of HCV inhibitors and outlining current therapeutic approaches to hepatitis C infection. Target identification involves studying a drug's mechanism of action (MOA), and a variety of target identification methods have been developed in the past few years. Chemical biology has emerged as a powerful tool for studying biological processes using small molecules. The use of chemical genetic methods is a valuable strategy for studying the molecular mechanisms of the viral lifecycle and screening for anti-viral agents. Two general screening approaches have been employed: forward and reverse chemical genetics. This review reveals information on the small molecules in HCV drug discovery by using chemical genetics for targeting the HCV protein and describes successful examples of targets identified with these methods.
Collapse
Affiliation(s)
- Guanghai Jin
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
| | - Jisu Lee
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea
| | - Kyeong Lee
- College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea.
| |
Collapse
|
|
28
|
Nielsen DS, Shepherd NE, Xu W, Lucke AJ, Stoermer MJ, Fairlie DP. Orally Absorbed Cyclic Peptides. Chem Rev 2017; 117:8094-8128. [PMID: 28541045 DOI: 10.1021/acs.chemrev.6b00838] [Citation(s) in RCA: 294] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol-water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.
Collapse
Affiliation(s)
- Daniel S Nielsen
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Nicholas E Shepherd
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Weijun Xu
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Andrew J Lucke
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - Martin J Stoermer
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| | - David P Fairlie
- Division of Chemistry and Structural Biology, and ‡Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland , Brisbane, QLD 4072, Australia
| |
Collapse
|
|
29
|
Steadman VA, Pettit SB, Poullennec KG, Lazarides L, Keats AJ, Dean DK, Stanway SJ, Austin CA, Sanvoisin JA, Watt GM, Fliri HG, Liclican AC, Jin D, Wong MH, Leavitt SA, Lee YJ, Tian Y, Frey CR, Appleby TC, Schmitz U, Jansa P, Mackman RL, Schultz BE. Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A. J Med Chem 2017; 60:1000-1017. [DOI: 10.1021/acs.jmedchem.6b01329] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Victoria A. Steadman
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Simon B. Pettit
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Karine G. Poullennec
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Linos Lazarides
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Andrew J. Keats
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - David K. Dean
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Steven J. Stanway
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Carol A. Austin
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Jonathan A. Sanvoisin
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Gregory M. Watt
- Selcia Ltd., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
| | - Hans G. Fliri
- Cypralis Ltd., Babraham Research
Campus, Cambridge CB22
3AT, United Kingdom
| | - Albert C. Liclican
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Debi Jin
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Melanie H. Wong
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Stephanie A. Leavitt
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Yu-Jen Lee
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Yang Tian
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Christian R. Frey
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Todd C. Appleby
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Uli Schmitz
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Petr Jansa
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Richard L. Mackman
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| | - Brian E. Schultz
- Gilead Sciences, 333 Lakeside
Drive, Foster City, California 94404, United States
| |
Collapse
|
|
30
|
Li T, Guo H, Zhao X, Jin J, Zhang L, Li H, Lu Y, Nie Y, Wu K, Shi Y, Fan D. Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop. Cancer Res 2016; 77:1227-1240. [PMID: 28011625 DOI: 10.1158/0008-5472.can-16-0357] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 11/08/2016] [Accepted: 11/12/2016] [Indexed: 11/16/2022]
Abstract
Molecular links between inflammation and cancer remain obscure despite their great pathogenic significance. The JAK2/STAT3 pathway activated by IL6 and other proinflammatory cytokines has garnered attention as a pivotal link in cancer pathogenesis, but the basis for its activation in cancer cells is not understood. Here we report that an IL6-triggered feedback loop involving STAT3-mediated suppression of miR-520d-5p and upregulation of its downstream target cyclophilin B (CypB) regulate the growth and survival of gastric cancer cells. In clinical specimens of gastric cancer, we documented increased expression of CypB and activation of STAT3. Mechanistic investigations identified miR-520d-5p as a regulator of CypB mRNA levels. This signaling axis regulated gastric cancer growth by modulating phosphorylation of STAT3. Furthermore, miR-520d-5p was identified as a direct STAT3 target and IL6-mediated inhibition of miR-520d-5p relied upon STAT3 activity. Our findings define a positive feedback loop that drives gastric carcinogenesis as influenced by H. pylori infections that involve proinflammatory IL6 stimulation. Cancer Res; 77(5); 1227-40. ©2016 AACR.
Collapse
Affiliation(s)
- Ting Li
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.,Department of Gastroenterology, The 264 Hospital of PLA, Taiyuan, China
| | - Hanqing Guo
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.,Department of Gastroenterology, Xi'an Central Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Xiaodi Zhao
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jiang Jin
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Lifeng Zhang
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Hong Li
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.,Department of Oncology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Yongquan Shi
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
| | - Daiming Fan
- State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
| |
Collapse
|
|
31
|
Dunyak BM, Gestwicki JE. Peptidyl-Proline Isomerases (PPIases): Targets for Natural Products and Natural Product-Inspired Compounds. J Med Chem 2016; 59:9622-9644. [PMID: 27409354 DOI: 10.1021/acs.jmedchem.6b00411] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Peptidyl-proline isomerases (PPIases) are a chaperone superfamily comprising the FK506-binding proteins (FKBPs), cyclophilins, and parvulins. PPIases catalyze the cis/trans isomerization of proline, acting as a regulatory switch during folding, activation, and/or degradation of many proteins. These "clients" include proteins with key roles in cancer, neurodegeneration, and psychiatric disorders, suggesting that PPIase inhibitors could be important therapeutics. However, the active site of PPIases is shallow, solvent-exposed, and well conserved between family members, making selective inhibitor design challenging. Despite these hurdles, macrocyclic natural products, including FK506, rapamycin, and cyclosporin, bind PPIases with nanomolar or better affinity. De novo attempts to derive new classes of inhibitors have been somewhat less successful, often showcasing the "undruggable" features of PPIases. Interestingly, the most potent of these next-generation molecules tend to integrate features of the natural products, including macrocyclization or proline mimicry strategies. Here, we review recent developments and ongoing challenges in the inhibition of PPIases, with a focus on how natural products might inform the creation of potent and selective inhibitors.
Collapse
Affiliation(s)
- Bryan M Dunyak
- Department of Biological Chemistry, University of Michigan Medical School , 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109, United States.,Department of Pharmaceutical Chemistry, University of California at San Francisco , 675 Nelson Rising Lane, San Francisco, California 94158, United States
| | - Jason E Gestwicki
- Department of Pharmaceutical Chemistry, University of California at San Francisco , 675 Nelson Rising Lane, San Francisco, California 94158, United States
| |
Collapse
|
|
32
|
Cuypers L, Snoeck J, Kerremans L, Libin P, Crabbé R, Van Dooren S, Vuagniaux G, Vandamme AM. HCV1b genome evolution under selective pressure of the cyclophilin inhibitor alisporivir during the DEB-025-HCV-203 phase II clinical trial. INFECTION GENETICS AND EVOLUTION 2016; 44:169-181. [PMID: 27374748 DOI: 10.1016/j.meegid.2016.06.050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 12/18/2022]
Abstract
Major advances have revolutionized the HCV antiviral treatment field, with interferon-free combinations of direct-acting antivirals (DAAs) resulting into success rates of >90% for all HCV genotypes. Nevertheless, viral eradication at a global level stills remains challenging, stimulating the continued search for new affordable pan-genotypic drugs. To overcome selection of drug resistant variants, targeting host proteins can be an attractive mechanism of action. Alisporivir (Debio 025) is a potent pan-genotypic host-targeting antiviral agent, acting on cyclophilin A, which is necessary for HCV replication. The efficacy and safety of three different oral doses of alisporivir in combination with pegylated interferon-α2a given over a period of four weeks, was investigated in a randomized, double-blind and placebo-controlled phase IIa clinical trial, in 90 treatment-naïve subjects infected with chronic hepatitis C, wherefrom 58 HCV1b samples were selected for genetic sequencing purposes. Sequencing results were used to study the HCV genome for amino acid changes potentially related with selective pressure and resistance to alisporivir. By comparing baseline and on-treatment sequences, a large variation in proportion of amino acid changes was detected in all treatment arms. The NS5A variant D320E, which was previously identified during in vitro resistance selection and resulted in 3.6-fold reduced alisporivir susceptibility, emerged in two subjects in the alisporivir monotherapy arm. However, emergence of D320E appeared to be associated only with concurrent viral load rebound in one subject with 0.8log10IU/ml increase in HCV RNA. In general, for all datasets, low numbers of positions under positive selective pressure were observed, with no significant differences between naïve and treated sequences. Additionally, incomplete sequence information for some of the 22 patients and the low number of individuals per treatment arm, is limiting the power to assess the association of alisporivir or interferon treatment with the observed amino acid changes.
Collapse
Affiliation(s)
- Lize Cuypers
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Joke Snoeck
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Lien Kerremans
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Pieter Libin
- Artificial Intelligence Lab, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Raf Crabbé
- Debiopharm International S.A., Che. Messidor 5-7, P.O. Box 5911, 1002 Lausanne, Switzerland.
| | - Sonia Van Dooren
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
| | - Grégoire Vuagniaux
- Debiopharm International S.A., Che. Messidor 5-7, P.O. Box 5911, 1002 Lausanne, Switzerland.
| | - Anne-Mieke Vandamme
- KU Leuven - University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Clinical and Epidemiological Virology, Minderbroedersstraat 10, 3000 Leuven, Belgium; Center for Global Health and Tropical Medicine, Unidade de Microbiologia, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Rua da Jungquiera 100, 1349-008 Lisbon, Portugal.
| |
Collapse
|
|
33
|
Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175. PLoS One 2016; 11:e0152036. [PMID: 27104614 PMCID: PMC4841536 DOI: 10.1371/journal.pone.0152036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 03/08/2016] [Indexed: 12/18/2022] Open
Abstract
Shortened current direct-acting antiviral (DAA) therapies while less expensive, have not provided satisfactory efficacy in naïve cirrhotics, treatment experienced non-cirrhotics or even genotype-3 (GT3)-infected patients. Since DAA regimens consist of the same classes of inhibitors—NS5A (NS5Ai) and NS5B (NS5Bi) +/- NS3 (NS3i) inhibitors—it is likely that their costs will be high and will provide similar degrees of protection. Integrating drugs with distinct mechanisms of action (MoA) into DAA regimens could provide the solution for shortening the period of treatment. One such class of agents is the cyclophilin inhibitors (CypI), which has shown efficacy in patients. Resistance-associated variants persist for years post-treatment in patients exposed to NS5Ai or NS5Bi who fail to achieve a sustained virologic response, impairing their chance for cure on retreatment with existing DAA combinations. Because of their high barrier to resistance, CypI may be particularly useful as a rescue therapy for patients who have relapsed with DAA resistance-associated variants. In this study, we analyzed the anti-HCV properties of the novel cyclosporine A (CsA) derivate—STG-175. The non-immunosuppressive STG-175 possesses a high (EC50 11.5–38.9 nM) multi-genotypic (GT1a to 4a) anti-HCV activity. STG-175 clears cells from HCV since no viral replication rebound was observed after cessation of drug treatment. It presents a higher barrier to resistance than other CypI or selected DAAs. HCV variants, which emerged under STG-175 pressure, are only ~2-fold resistant to the drug. No cross-resistance was observed with DAAs STG-175 was efficacious against DAA-resistant HCV variants. Drug combination studies revealed that STG-175 provides additive and synergistic effects against GT1a to 4a. STG-175 inhibits the infection of HCV, HIV-1 and HBV in mono-, dual- and triple-infection settings. Altogether these results suggest that the new CypI STG-175 represents an attractive drug partner for IFN-free DAA regimens for the treatment of HCV and co-infections.
Collapse
|
|
34
|
Scherer ML, Sammons C, Nelson B, Hammer SM, Verna E. Anti-Hepatitis Virus Agents. CLINICAL VIROLOGY 2016:239-270. [DOI: 10.1128/9781555819439.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
35
|
Khachatoorian R, French SW. Chaperones in hepatitis C virus infection. World J Hepatol 2016; 8:9-35. [PMID: 26783419 PMCID: PMC4705456 DOI: 10.4254/wjh.v8.i1.9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 10/01/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
The hepatitis C virus (HCV) infects approximately 3% of the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 deaths occur worldwide due to HCV-associated diseases including cirrhosis and hepatocellular carcinoma. HCV is the most common indication for liver transplantation in patients with cirrhosis worldwide. HCV is an enveloped RNA virus classified in the genus Hepacivirus in the Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases: (1) binding and internalization; (2) cytoplasmic release and uncoating; (3) viral polyprotein translation and processing; (4) RNA genome replication; (5) encapsidation (packaging) and assembly; and (6) virus morphogenesis (maturation) and secretion. Many host factors are involved in the HCV life cycle. Chaperones are an important group of host cytoprotective molecules that coordinate numerous cellular processes including protein folding, multimeric protein assembly, protein trafficking, and protein degradation. All phases of the viral life cycle require chaperone activity and the interaction of viral proteins with chaperones. This review will present our current knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV infection will provide further insights into viral/host interactions and potential therapeutic targets for both HCV and other viruses.
Collapse
|
|
36
|
|
|
37
|
Hopkins S, Gallay PA. The role of immunophilins in viral infection. Biochim Biophys Acta Gen Subj 2015; 1850:2103-10. [PMID: 25445708 PMCID: PMC4491039 DOI: 10.1016/j.bbagen.2014.11.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/11/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND Tremendous progress has been made in the past 20 years in understanding the roles played by immunophilins, and in particular the cyclophilins, in supporting the replication cycles of human viruses. A growing body of genetic and biochemical evidence and data from clinical trials confirm that cyclophilins are essential cofactors that contribute to establishing a permissive environment within the host cell that supports the replication of HIV-1 and HCV. Cyclophilin A regulates HIV-1 replication kinetics and infectivity, modulates sensitivity to host restriction factors, and cooperates in the transit of the pre-integration complex into the nucleus of infected cells. Cyclophilin A is an essential cofactor whose expression supports HCV-specific RNA replication in human hepatocytes. GENERAL SIGNIFICANCE Peptidyl-prolyl isomerase inhibitors have been used in clinical trials to validate cyclophilins as antiviral targets for the treatment of HIV-1 and Chronic Hepatitis C virus infection and as molecular probes to identify the roles played by immunophilins in supporting the replication cycles of human viruses. SCOPE OF REVIEW This review summarizes emerging research that defines the functions of immunophilins in supporting the replication cycles of HIV-1, HCV, HBV, coronaviruses, and other viral pathogens and describes new information that suggests a role for immunophilins in regulating innate immune responses against chronic viral infection. MAJOR CONCLUSIONS The dependence on cyclophilins by evolutionarily distinct viruses for accomplishing various steps in replication such as viral entry, initiation of genomic nucleic acid replication, viral genome uncoating, nuclear import and nuclear entry, emphasizes the potential of cyclophilin inhibitors as therapeutic agents. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.
Collapse
Affiliation(s)
- Sam Hopkins
- Department of Clinical Research, Autoimmune Technologies, New Orleans, LA 70112 USA.
| | - Philippe A Gallay
- Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
| |
Collapse
|
|
38
|
Gallay PA, Bobardt MD, Chatterji U, Trepanier DJ, Ure D, Ordonez C, Foster R. The Novel Cyclophilin Inhibitor CPI-431-32 Concurrently Blocks HCV and HIV-1 Infections via a Similar Mechanism of Action. PLoS One 2015; 10:e0134707. [PMID: 26263487 PMCID: PMC4532424 DOI: 10.1371/journal.pone.0134707] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 07/13/2015] [Indexed: 12/17/2022] Open
Abstract
HCV-related liver disease is the main cause of morbidity and mortality of HCV/HIV-1 co-infected patients. Despite the recent advent of anti-HCV direct acting antivirals (DAAs), the treatment of HCV/HIV-1 co-infected patients remains a challenge, as these patients are refractory to most therapies and develop liver fibrosis, cirrhosis and liver cancer more often than HCV mono-infected patients. Until the present study, there was no suitable in vitro assay to test the inhibitory activity of drugs on HCV/HIV-1 co-infection. Here we developed a novel in vitro "co-infection" model where HCV and HIV-1 concurrently replicate in their respective main host target cells--human hepatocytes and CD4+ T-lymphocytes. Using this co-culture model, we demonstrate that cyclophilin inhibitors (CypI), including a novel cyclosporin A (CsA) analog, CPI-431-32, simultaneously inhibits replication of both HCV and HIV-1 when added pre- and post-infection. In contrast, the HIV-1 protease inhibitor nelfinavir or the HCV NS5A inhibitor daclatasvir only blocks the replication of a single virus in the "co-infection" system. CPI-431-32 efficiently inhibits HCV and HIV-1 variants, which are normally resistant to DAAs. CPI-431-32 is slightly, but consistently more efficacious than the most advanced clinically tested CypI--alisporivir (ALV)--at interrupting an established HCV/HIV-1 co-infection. The superior antiviral efficacy of CPI-431-32 over ALV correlates with its higher potency inhibition of cyclophilin A (CypA) isomerase activity and at preventing HCV NS5A-CypA and HIV-1 capsid-CypA interactions known to be vital for replication of the respective viruses. Moreover, we obtained evidence that CPI-431-32 prevents the cloaking of both the HIV-1 and HCV genomes from cellular sensors. Based on these results, CPI-431-32 has the potential, as a single agent or in combination with DAAs, to inhibit both HCV and HIV-1 infections.
Collapse
Affiliation(s)
- Philippe A. Gallay
- Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Michael D. Bobardt
- Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Udayan Chatterji
- Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Daniel J. Trepanier
- Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America
| | - Daren Ure
- Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America
| | - Cosme Ordonez
- Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America
| | - Robert Foster
- Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America
| |
Collapse
|
|
39
|
Cyclophilin and NS5A inhibitors, but not other anti-hepatitis C virus (HCV) agents, preclude HCV-mediated formation of double-membrane-vesicle viral factories. Antimicrob Agents Chemother 2015; 59:2496-507. [PMID: 25666154 DOI: 10.1128/aac.04958-14] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Accepted: 02/02/2015] [Indexed: 12/14/2022] Open
Abstract
Although the mechanisms of action (MoA) of nonstructural protein 3 inhibitors (NS3i) and NS5B inhibitors (NS5Bi) are well understood, the MoA of cyclophilin inhibitors (CypI) and NS5A inhibitors (NS5Ai) are not fully defined. In this study, we examined whether CypI and NS5Ai interfere with hepatitis C virus (HCV) RNA synthesis of replication complexes (RCs) or with an earlier step of HCV RNA replication, the creation of double-membrane vesicles (DMVs) essential for HCV RNA replication. In contrast to NS5Bi, both CypI and NS5Ai do not block HCV RNA synthesis by way of RCs, suggesting that they exert their antiviral activity prior to the establishment of enzymatically active RCs. We found that viral replication is not a precondition for DMV formation, since the NS3-NS5B polyprotein or NS5A suffices to create DMVs. Importantly, only CypI and NS5Ai, but not NS5Bi, mir-122, or phosphatidylinositol-4 kinase IIIα (PI4KIIIα) inhibitors, prevent NS3-NS5B-mediated DMV formation. NS3-NS5B was unable to create DMVs in cyclophilin A (CypA) knockdown (KD) cells. We also found that the isomerase activity of CypA is absolutely required for DMV formation. This not only suggests that NS5A and CypA act in concert to build membranous viral factories but that CypI and NS5Ai mediate their early anti-HCV effects by preventing the formation of organelles, where HCV replication is normally initiated. This is the first investigation to examine the effect of a large panel of anti-HCV agents on DMV formation, and the results reveal that CypI and NS5Ai act at the same membranous web biogenesis step of HCV RNA replication, thus indicating a new therapeutic target of chronic hepatitis C.
Collapse
|
|
40
|
Phillips S, Chokshi S, Chatterji U, Riva A, Bobardt M, Williams R, Gallay P, Naoumov NV. Alisporivir inhibition of hepatocyte cyclophilins reduces HBV replication and hepatitis B surface antigen production. Gastroenterology 2015; 148:403-14.e7. [PMID: 25305505 PMCID: PMC7172380 DOI: 10.1053/j.gastro.2014.10.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Revised: 09/15/2014] [Accepted: 10/05/2014] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Cyclophilins are host factors required for hepatitis C virus replication. Cyclophilin inhibitors such as alisporivir have shown strong anti-hepatitis C virus activity in vitro and in clinical studies. However, little is known about whether hepatocyte cyclophilins are involved in the hepatitis B virus (HBV) life cycle. We investigated the effects of 2 cyclophilin inhibitors (alisporivir and NIM811) on HBV replication and hepatitis B surface antigen (HBsAg) production in cell lines. METHODS Liver-derived cell lines producing full-length HBV and HBsAg particles, owing to stable (HepG2215) or transient (HuH-7) transfection, or infected with HBV (HepaRG cells; Invitrogen [Carlsbad, CA]), were incubated with alisporivir or NIM811 alone, or alisporivir in combination with a direct antiviral (telbivudine). The roles of individual cyclophilins in drug response was evaluated by small interfering RNA knockdown of cyclophilin (CYP)A, CYPC, or CYPD in HepG2215 cells, or CYPA knockdown in HuH-7 cells. The kinetics of antiviral activity were assessed based on levels of HBV DNA and HBsAg and Southern blot analysis. RESULTS In HepG2215, HuH-7, and HepaRG cells, alisporivir reduced intracellular and secreted HBV DNA, in a dose-dependent manner. Knockdown of CYPA, CYPC, or CYPD (reduced by 80%) significantly reduced levels of HBV DNA and secreted HBsAg. Knockdown of CYPA significantly reduced secretion of HBsAg, leading to accumulation of intracellular HBsAg; the addition of alisporivir greatly reduced levels of HBsAg in these cells. The combination of alisporivir and telbivudine had greater antiviral effects than those of telbivudine or alisporivir alone. CONCLUSIONS Alisporivir inhibition of cyclophilins in hepatocyte cell lines reduces replication of HBV DNA and HBsAg production and secretion. These effects are potentiated in combination with direct antiviral agents that target HBV-DNA polymerase.
Collapse
Affiliation(s)
- Sandra Phillips
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Shilpa Chokshi
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Udayan Chatterji
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California
| | - Antonio Riva
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Michael Bobardt
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California
| | - Roger Williams
- Institute of Hepatology, Foundation for Liver Research, London, United Kingdom
| | - Philippe Gallay
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California
| | - Nikolai V. Naoumov
- Novartis Pharma AG, Basel, Switzerland,Reprint requests Address requests for reprints to: Nikolai V. Naoumov, MD, PhD, Novartis Pharma AG, Fabrikstrasse 6, WSJ157.4, CH-Basel 4002, Switzerland. fax: (41) 61-324 9439
| |
Collapse
|
|
41
|
Bioengineering and semisynthesis of an optimized cyclophilin inhibitor for treatment of chronic viral infection. ACTA ACUST UNITED AC 2015; 22:285-92. [PMID: 25619934 PMCID: PMC4336584 DOI: 10.1016/j.chembiol.2014.10.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 10/08/2014] [Accepted: 10/22/2014] [Indexed: 12/11/2022]
Abstract
Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.
Optimization and preclinical analysis of a bacterial natural product Combination of bioengineering and semisynthetic chemistry Preclinical analysis revealing potent antiviral activity
Collapse
|
|
42
|
Nath PR, Isakov N. Insights into peptidyl-prolyl cis–trans isomerase structure and function in immunocytes. Immunol Lett 2015; 163:120-31. [DOI: 10.1016/j.imlet.2014.11.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 10/27/2014] [Accepted: 11/03/2014] [Indexed: 12/30/2022]
|
|
43
|
Tedbury PR, Freed EO. HIV-1 gag: an emerging target for antiretroviral therapy. Curr Top Microbiol Immunol 2015; 389:171-201. [PMID: 25731773 DOI: 10.1007/82_2015_436] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
The advances made in the treatment of HIV-1 infection represent a major success of modern biomedical research, prolonging healthy life and reducing virus transmission. There remain, however, many challenges relating primarily to side effects of long-term therapy and the ever-present danger of the emergence of drug-resistant strains. To counter these threats, there is a continuing need for new and better drugs, ideally targeting multiple independent steps in the HIV-1 replication cycle. The most successful current drugs target the viral enzymes: protease (PR), reverse transcriptase (RT), and integrase (IN). In this review, we outline the advances made in targeting the Gag protein and its mature products, particularly capsid and nucleocapsid, and highlight possible targets for future pharmacological intervention.
Collapse
Affiliation(s)
- Philip R Tedbury
- Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute, Center for Cancer Research, Frederick, MD, 21702-1201, USA
| | | |
Collapse
|
|
44
|
Lawen A. Biosynthesis of cyclosporins and other natural peptidyl prolyl cis/trans isomerase inhibitors. Biochim Biophys Acta Gen Subj 2014; 1850:2111-20. [PMID: 25497210 DOI: 10.1016/j.bbagen.2014.12.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 12/01/2014] [Accepted: 12/04/2014] [Indexed: 01/11/2023]
Abstract
BACKGROUND Peptidyl-prolyl-cis/trans-isomerases (PPIases) are ubiquitously expressed and have been implicated in a wide range of biological functions. Their inhibition is beneficial in immunosuppression, cancer treatment, treatment of autoimmune diseases, protozoan and viral infections. SCOPE OF REVIEW Three classes of PPIases are known, each class having their own specific inhibitors. This review will cover the present knowledge on the biosynthesis of the natural PPIase inhibitors. These include for the cyclophilins: the cyclosporins, the analogues of peptolide SDZ 214-103 and the sanglifehrins; for the FKBPs: ascomycin, rapamycin and FK506 and for the parvulins the naphtoquinone juglone. MAJOR CONCLUSIONS Over the last thirty years much progress has been made in understanding PPIase function and the biosynthesis of natural PPIase inhibitors. Non-immunosuppressive analogues were discovered and served as lead compounds for the development of novel antiviral drugs. There are, however, still unsolved questions which deserve further research into this exciting field. GENERAL SIGNIFICANCE As all the major natural inhibitors of the cyclophilins and FKBPs are synthesized by complex non-ribosomal peptide synthetases and/or polyketide synthases, total chemical synthesis is not a viable option. Thus, fully understanding the modular enzyme systems involved in their biosynthesis may help engineering enzymes capable of synthesizing novel PPIase inhibitors with improved functions for a wide range of conditions. This article is part of a Special Issue entitled Proline-directed Foldases: Cell signaling catalysts and drug targets.
Collapse
Affiliation(s)
- Alfons Lawen
- Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Victoria 3800, Australia.
| |
Collapse
|
|
45
|
Serranti D, Indolfi G, Resti M. New treatments for chronic hepatitis C: an overview for paediatricians. World J Gastroenterol 2014; 20:15965-74. [PMID: 25473150 PMCID: PMC4239484 DOI: 10.3748/wjg.v20.i43.15965] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 06/23/2014] [Accepted: 08/13/2014] [Indexed: 02/06/2023] Open
Abstract
Pegylated interferon (IFN) α-2a or 2b in combination with ribavirin for children aged 3 years and older is the standard treatment for paediatric chronic hepatitis C. This treatment regimen was developed firstly in adults. In recent years, a number of direct-acting antiviral agents (DAAs) are under development for treatment of chronic hepatitis C virus (HCV) infection. These agents block viral replication inhibiting directly one of the several steps of HCV lifecycle. DAAs are classified into several categories based on their molecular target: HCV NS3/4A protease inhibitors, HCV NS5B polymerase inhibitors and HCV NS5A inhibitors. Other promising compounds are cyclophilin A inhibitors, mi-RNA122 and IFN-λ. Several new drugs associations will be developed in the near future starting from the actual standard of care. IFN-based and IFN-free regimens are being studied in adults. In this constantly evolving scenario new drug regimens targeted and suitable for children would be possible in the next future. Especially for children, it is crucial to identify the right combination of drugs with the highest potency, barrier to resistance and the best safety profile.
Collapse
|
|
46
|
Shahid I, ALMalki WH, Hafeez MH, Hassan S. Hepatitis C virus infection treatment: An era of game changer direct acting antivirals and novel treatment strategies. Crit Rev Microbiol 2014; 42:535-47. [PMID: 25373616 DOI: 10.3109/1040841x.2014.970123] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus infection and associated liver diseases represent a major health care burden all over the world. The current standard of care, i.e. peginterferon-alfa (PEG-IFNα) plus ribavirin (RBV) are associated with frequent and sometimes serious adverse effects and contraindications, which further limit their therapeutic efficacy. The approval of first and second generation HCV protease inhibitors represents a major breakthrough in the development of novel direct acting antivirals (DAAs) against different HCV genotypes and establishes a new standard of care for chronically infected HCV genotypes 1 patients. Similarly, next generation protease inhibitors and HCV RNA polymerase inhibitors have shown better pharmacokinetics and pharmacodynamics in terms of broader HCV genotypes coverage, better safety profile, fewer drug interactions and possible once daily administration than first generation direct acting antivirals. The testing of adenovirus-based vector vaccines, which escalates the innate and acquired immune responses against the most conserved regions of the HCV genome in chimpanzees and humans, may be a promising therapeutic approach against HCV infection in coming future. This review article presents up-to-date knowledge and recent developments in HCV therapeutics, insights the shortcomings of current HCV therapies and key lessons from the therapeutic potential of improved anti-HCV treatment strategies.
Collapse
Affiliation(s)
- Imran Shahid
- a Department of Molecular Biology , Applied and Functional Genomics Lab, CEMB, University of the Punjab , Near Thokar Niaz Baig , Lahore , Pakistan .,b Department of Pharmacology and Toxicology , College of Pharmacy, Umm Al Qura University , Al-Abidiyah , Makkah , Saudi Arabia
| | - Waleed Hassan ALMalki
- b Department of Pharmacology and Toxicology , College of Pharmacy, Umm Al Qura University , Al-Abidiyah , Makkah , Saudi Arabia
| | - Muhammad Hassan Hafeez
- c Department of Gastroenterology and Hepatology , Fatima Memorial Hospital and College of Medicine and Dentistry , Shadman , Lahore , Pakistan , and
| | - Sajida Hassan
- a Department of Molecular Biology , Applied and Functional Genomics Lab, CEMB, University of the Punjab , Near Thokar Niaz Baig , Lahore , Pakistan .,d Viral Hepatitis Program, Laboratory of Medicine, University of Washington , Seattle , WA , USA
| |
Collapse
|
|
47
|
Eyre NS, Helbig KJ, Beard MR. Current and future targets of antiviral therapy in the hepatitis C virus life cycle. Future Virol 2014. [DOI: 10.2217/fvl.14.83] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
ABSTRACT Advances in our understanding of the hepatitis C virus (HCV) life cycle have enabled the development of numerous clinically advanced direct-acting antivirals. Indeed, the recent approval of first-generation direct-acting antivirals that target the viral NS3–4A protease and NS5B RNA-dependent RNA polymerase brings closer the possibility of universally efficacious and well-tolerated antiviral therapies for this insidious infection. However, the complexities of comorbidities, unforeseen side effects or drug–drug interactions, viral diversity, the high mutation rate of HCV RNA replication and the elegant and constantly evolving mechanisms employed by HCV to evade host and therapeutically implemented antiviral strategies remain as significant obstacles to this goal. Here, we review advances in our understanding of the HCV life cycle and associated opportunities for antiviral therapy.
Collapse
Affiliation(s)
- Nicholas S Eyre
- School of Molecular & Biomedical Science, The University of Adelaide & Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia
| | - Karla J Helbig
- School of Molecular & Biomedical Science, The University of Adelaide & Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia
| | - Michael R Beard
- School of Molecular & Biomedical Science, The University of Adelaide & Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia
| |
Collapse
|
|
48
|
Lim PJ, Gallay PA. Hepatitis C NS5A protein: two drug targets within the same protein with different mechanisms of resistance. Curr Opin Virol 2014; 8:30-7. [PMID: 24879295 PMCID: PMC4195798 DOI: 10.1016/j.coviro.2014.04.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Revised: 04/29/2014] [Accepted: 04/30/2014] [Indexed: 12/18/2022]
Abstract
The era of interferon-free antiviral treatments for hepatitis C virus infection has arrived. With increasing numbers of approved antivirals, evaluating all parameters that may influence response is necessary to choose optimal combinations for treatment success. Targeting NS5A has become integral in antiviral combinations in clinical development. Daclatasvir and ledipasvir belong to the NS5A inhibitor class, which directly target the NS5A protein. Alisporivir, a host-targeting antiviral, is a cyclophilin inhibitor that indirectly targets NS5A by blocking NS5A/cyclophilin A interaction. Resistance to daclatasvir and ledipasvir differs from alisporivir, with mutations arising in NS5A domains I and II, respectively. Combining these two classes acting on distinct NS5A domains represents an attractive strategy for potentially effective interferon-free treatments for chronic hepatitis C infection.
Collapse
Affiliation(s)
- Precious J Lim
- Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Philippe A Gallay
- Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
| |
Collapse
|
|
49
|
A pharmacokinetic-viral kinetic model describes the effect of alisporivir as monotherapy or in combination with peg-IFN on hepatitis C virologic response. Clin Pharmacol Ther 2014; 96:599-608. [PMID: 25166216 DOI: 10.1038/clpt.2014.173] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 07/31/2014] [Indexed: 12/12/2022]
Abstract
Alisporivir is a cyclophilin inhibitor with demonstrated in vitro and in vivo activity against hepatitis C virus (HCV). We estimated the antiviral effectiveness of alisporivir alone or in combination with pegylated interferon (peg-IFN) in 88 patients infected with different HCV genotypes treated for 4 weeks. The pharmacokinetics of the two drugs were modeled and used as driving functions for the viral kinetic model. Genotype was found to significantly affect peg-IFN effectiveness (ɛ = 86.3 and 99.1% for genotypes 1/4 and genotypes 2/3, respectively, P < 10(-7)) and the loss rate of infected cells (δ = 0.22 vs. 0.39 per day in genotype 1/4 and genotype 2/3 patients, respectively, P < 10(-6)). Alisporivir effectiveness was not significantly different across genotypes and was high for doses ≥600 mg q.d. We simulated virologic responses with other alisporivir dosing regimens in HCV genotype 2/3 patients using the model. Our predictions consistently matched the observed responses, demonstrating that this model could be a useful tool for anticipating virologic response and optimizing alisporivir-based therapies.
Collapse
|
|
50
|
Abstract
Dengue virus (DENV) is an emerging mosquito-borne human pathogen that affects millions of individuals each year by causing severe and potentially fatal syndromes. Despite intense research efforts, no approved vaccine or antiviral therapy is yet available. Overcoming this limitation requires detailed understanding of the intimate relationship between the virus and its host cell, providing the basis to devise optimal prophylactic and therapeutic treatment options. With the advent of novel high-throughput technologies including functional genomics, transcriptomics, proteomics, and lipidomics, new important insights into the DENV replication cycle and the interaction of this virus with its host cell have been obtained. In this chapter, we provide a comprehensive overview on the current status of the DENV research field, covering every step of the viral replication cycle with a particular focus on virus-host cell interaction. We will also review specific chemical inhibitors targeting cellular factors and processes of relevance for the DENV replication cycle and their possible exploitation for the development of next generation antivirals.
Collapse
|