Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture

被引：52

作者：

Bafna, Khushboo ^{[1
,2
]}

White, Kris ^{[3
,4
]}

Harish, Balasubramanian ^{[2
,5
]}

Rosales, Romel ^{[3
,4
]}

Ramelot, Theresa A. ^{[1
,2
]}

Acton, Thomas B. ^{[1
,2
]}

Moreno, Elena ^{[3
,4
]}

Kehrer, Thomas ^{[3
,4
]}

Miorin, Lisa ^{[3
,4
]}

Royer, Catherine A. ^{[2
,5
]}

Garcia-Sastre, Adolfo ^{[3
,4
,6
,7
]}

Krug, Robert M. ^{[8
]}

Montelione, Gaetano T. ^{[1
,2
]}

机构：

[1] Rensselaer Polytech Inst, Dept Chem & Chem Biol, Troy, NY 12180 USA

[2] Rensselaer Polytech Inst, Ctr Biotechnol & Interdisciplinary Sci, Troy, NY 12180 USA

[3] Icahn Sch Med Mt Sinai, Dept Microbiol, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Global Hlth & Emerging Pathogens Inst, New York, NY 10029 USA

[5] Rensselaer Polytech Inst, Dept Biol, Troy, NY 12180 USA

[6] Icahn Sch Med Mt Sinai, Dept Med, Div Infect Dis, New York, NY 10029 USA

[7] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

[8] Univ Texas Austin, John Ring LaMontagne Ctr Infect Dis, Inst Cellular & Mol Biol, Dept Mol Biosci, Austin, TX 78712 USA

来源：

CELL REPORTS | 2021年 / 35卷 / 07期

基金：

美国国家卫生研究院;

关键词：

SARS-CORONAVIRUS; DOCKING; ISG15; COMBINATION; SEQUENCE; BINDING;

D O I：

10.1016/j.celrep.2021.109133

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Effective control of COVID-19 requires antivirals directed against SARS-CoV-2. We assessed 10 hepatitis C virus (HCV) protease-inhibitor drugs as potential SARS-CoV-2 antivirals. There is a striking structural similarity of the substrate binding clefts of SARS-CoV-2 main protease (M-pro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the M-pro substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 M-pro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their M-pro inhibiting activities did not correlate with their antiviral activities. This conundrum is resolved by demonstrating that four HCV protease inhibitor drugs, simeprevir, vaniprevir, paritaprevir, and grazoprevir inhibit the SARS CoV-2 papain-like protease (PLpro). HCV drugs that inhibit PLpro synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing remdesivir's antiviral activity as much as 10-fold, while those that only inhibit M-pro do not synergize with remdesivir.

引用

页数：20

共 54 条

[1]

Amanat Fatima, 2020, Curr Protoc Microbiol, V58, pe108, DOI 10.1002/cpmc.108

[2] Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain [J].