Drug repurposing through virtual screening and in vitro validation identifies tigecycline as a novel putative HCV polymerase inhibitor

Mahmoud ElHefnawi; Eunji Jo; Mahmoud M Tolba; Mohamed Fares; Jaewon Yang; Mohd Shahbaaz; Marc P Windisch

doi:10.1016/j.virol.2022.02.006

Drug repurposing through virtual screening and in vitro validation identifies tigecycline as a novel putative HCV polymerase inhibitor

Virology. 2022 May:570:9-17. doi: 10.1016/j.virol.2022.02.006. Epub 2022 Mar 10.

Authors

Mahmoud ElHefnawi¹, Eunji Jo², Mahmoud M Tolba¹, Mohamed Fares³, Jaewon Yang², Mohd Shahbaaz⁴, Marc P Windisch⁵

Affiliations

¹ Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt.
² Applied Molecular Virology Laboratory, Discovery Biology Division, Institut Pasteur Korea, Sampyung-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea.
³ Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt; Center for Informatics Science (CIS), Nile University, Juhayna Square, Sheikh Zayed City, Giza, Egypt.
⁴ South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, South Africa; Laboratory of Computational Modeling of Drugs, South Ural State University, Chelyabinsk, Russia.
⁵ Applied Molecular Virology Laboratory, Discovery Biology Division, Institut Pasteur Korea, Sampyung-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, South Korea; Division of Bio-Medical Science and Technology, University of Science and Technology, Yuseong-gu, Daejeon, South Korea. Electronic address: marc.windisch@ip-korea.org.

PMID: 35338891
DOI: 10.1016/j.virol.2022.02.006

Abstract

The repurposing of marketed drugs for new indications is an elegant strategy to quickly and cost-efficiently address unmet medical needs. The hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) has been shown to be a valid drug target. We performed structure-based virtual screening to assess the off-label utilization of existing drugs as novel HCV inhibitors. The virtual screen showed that tigecycline could potentially dock with high affinity to the palm site of the HCV RdRp. In vitro validation showed that tigecycline had therapeutic indexes (CC₅₀/EC₅₀) greater than 13 and 6.5 against infectious HCV and subgenomic HCV replicons, respectively. Furthermore, tigecycline displayed synergistic activity with sofosbuvir and daclatasvir against HCV. In silico screening identified tigecycline as a putative inhibitor of HCV RdRp, which was validated in vitro and demonstrated synergistic effects in combination with first-line anti-HCV therapies.

Keywords: Direct-acting antivirals; Drug repurposing; Drug-drug combinations; HCV replicon; Hepatitis C virus; In silico; In vitro; Infectious HCV; NS5B polymerase; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology
Drug Repositioning
Hepacivirus* / genetics
Hepatitis C*
Humans
RNA-Dependent RNA Polymerase / genetics
Tigecycline / pharmacology
Viral Nonstructural Proteins / genetics
Virus Replication

Substances

Antiviral Agents
Viral Nonstructural Proteins
Tigecycline
RNA-Dependent RNA Polymerase