Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture.
Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture.
复制标题
DOI：
10.1016/j.celrep.2021.109133
复制
发表时间：
2021-05-18
期刊：
影响因子：
8.8
通讯作者：
Montelione GT
中科院分区：
文献类型：
--
作者：
Bafna K;White K;Harish B;Rosales R;Ramelot TA;Acton TB;Moreno E;Kehrer T;Miorin L;Royer CA;García-Sastre A;Krug RM;Montelione GT
有效控制COVID-19需要针对SARS-CoV-2的抗病毒药物。我们评估了10种丙型肝炎病毒（HCV）蛋白酶抑制剂药物作为潜在的SARS-CoV-2抗病毒药物。SARS-CoV-2主要蛋白酶（Mpro）与HCV NS 3/4A蛋白酶的底物结合裂缝具有惊人的结构相似性。虚拟对接实验表明，这些HCV药物可以潜在地结合到Mpro底物结合裂缝中。我们发现，7种HCV药物抑制SARS-CoV-2 Mpro蛋白酶活性和SARS-CoV-2病毒在Vero细胞和/或人细胞中的复制。然而，它们的Mpro抑制活性与它们的抗病毒活性无关。通过证明四种HCV蛋白酶抑制剂药物，simeprevir，vaniprevir，paritaprevir和grazoprevir抑制SARS CoV-2木瓜蛋白酶样蛋白酶（PLpro），解决了这个难题。抑制PLpro的HCV药物与病毒聚合酶抑制剂remdesivir协同作用以抑制病毒复制，使remdesivir的抗病毒活性增加多达10倍，而那些仅抑制Mpro的药物不与remdesivir协同作用。Bafna等人报道了几种可用的丙型肝炎病毒药物抑制SARS-CoV-2 Mpro和/或PLpro蛋白酶和SARS-CoV-2在细胞培养物中的复制。抑制PLpro酶活性的四种HCV药物也与Remdesivir协同作用，抑制病毒复制，增加Remdesivir和HCV药物的抗病毒活性。
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 (Mpro) and HCV NS3/4A protease. Virtual docking experiments show that these HCV drugs can potentially bind into the Mpro substrate-binding cleft. We show that seven HCV drugs inhibit both SARS-CoV-2 Mpro protease activity and SARS-CoV-2 virus replication in Vero and/or human cells. However, their Mpro 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 Mpro do not synergize with remdesivir. Bafna et al. report that several available hepatitis C virus drugs inhibit the SARS-CoV-2 Mpro and/or PLpro proteases and SARS-CoV-2 replication in cell culture. The four HCV drugs that inhibit PLpro enzyme activity also synergize with remdesivir to inhibit virus replication, increasing the antiviral activity of remdesivir and HCV drugs.
登录
查看更多内容
影响因子：
14.9
作者：
Gorbalenya AE;Koonin EV;Donchenko AP;Blinov VM
通讯作者：
Blinov VM
新的配体和靶标的对接和化学信息筛选。
影响因子：
7.7
作者：
Kolb, Peter;Ferreira, Rafaela S.;Irwin, John J.;Shoichet, Brian K.
通讯作者：
Shoichet, Brian K.
SARS冠状病毒蛋白酶样蛋白酶的ISG15和泛素识别的选择性。
影响因子：
3.9
作者：
Lindner HA;Lytvyn V;Qi H;Lachance P;Ziomek E;Ménard R
通讯作者：
Ménard R
冠状病毒主蛋白酶的结构揭示了甲over依蛋白酶折叠与额外的α-螺旋结构域的组合。
影响因子：
11.4
作者：
Anand, Kanchan;Palm, Gottfried J;Mesters, Jeroen R;Siddell, Stuart G;Ziebuhr, John;Hilgenfeld, Rolf
通讯作者：
Hilgenfeld, Rolf
影响因子：
5
作者：
Grum-Tokars, Valerie;Ratia, Kiira;Begaye, Adrian;Baker, Susan C.;Mesecar, Andrew D.
通讯作者：
Mesecar, Andrew D.