Opinion Review
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2019; 25(15): 1783-1796
Published online Apr 21, 2019. doi: 10.3748/wjg.v25.i15.1783
Repurposing drugs to target nonalcoholic steatohepatitis
Silvia Sookoian, Carlos J Pirola
Silvia Sookoian, Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires 1427, Argentina
Carlos J Pirola, Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autonoma de Buenos Aires 1427, Argentina
Author contributions: All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version, Sookoian S and Pirola CJ should be considered joint senior authors.
Supported by grants PICT 2014-0432, PICT 2014-1816 and PICT 2015-0551, PICT 2016-0135 (Agencia Nacional de Promoción Científica y Tecnológica, FONCyT).
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Silvia Sookoian, FAASLD, MD, PhD, Senior Scientist, Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Combatientes de Malvinas 3150, Ciudad Autónoma de Buenos Aires 1427, Argentina. ssookoian@intramed.net
Telephone: +54-11-52873905 Fax: +54-11-52873905
Received: January 18, 2019
Peer-review started: January 18, 2019
First decision: March 20, 2019
Revised: March 21, 2019
Accepted: March 29, 2019
Article in press: March 30, 2019
Published online: April 21, 2019
Processing time: 90 Days and 12.7 Hours
Abstract

Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases (phase 1 and 2), which involve testing tolerability, therapeutic action, and pharmacological issues. It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.

Keywords: Drug discovery; Drug repositioning; Fibrosis; Genetics; Treatment; Systems biology

Core tip: As a proof-of-concept of the advantages that can be yielded by applying multi-omics systems-based approaches to the analysis of potential candidates to the treatment of nonalcoholic steatohepatitis (NASH) we selected the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway map of nonalcoholic fatty liver disease (NAFLD), which illustrates a stage-dependent progression of the disease. After generating a protein−chemical interaction network, we predicted remarkable examples of potential drug repurposing for the treatment of NASH based on the NAFLD-KEGG connectivity map.