Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2
| Autor: | Yuyong Zhou, Troels K. H. Scheel, Shan Feng, Jens Bukh, Karen A. Gammeltoft, Santseharay Ramirez, Judith M. Gottwein, Long V. Pham, Anna Offersgaard, Andrea Galli, Rui Costa, Carlos Rene Duarte Hernandez, Ulrik Fahnøe |
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| Rok vydání: | 2021 |
| Předmět: |
Viral Protease Inhibitors
Voxilaprevir Vaniprevir viruses coronavirus repurposing synergy Hepacivirus Antiviral Agents Telaprevir chemistry.chemical_compound Boceprevir Chlorocebus aethiops medicine Animals Humans Pharmacology (medical) Protease Inhibitors Vero Cells Pharmacology Alanine SARS-CoV-2 Danoprevir virus diseases COVID-19 Glecaprevir Hepatitis C Chronic Virology Hepatitis C antiviral Adenosine Monophosphate COVID-19 Drug Treatment Infectious Diseases Grazoprevir chemistry Narlaprevir Spike Glycoprotein Coronavirus combination treatment medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy Gammeltoft, K A, Zhou, Y, Duarte Hernandez, C R, Galli, A, Offersgaard, A, Costa, R, Pham, L V, Fahnøe, U, Feng, S, Scheel, T K H, Ramirez, S, Bukh, J & Gottwein, J M 2021, ' Hepatitis C Virus Protease Inhibitors Show Differential Efficacy and Interactions with Remdesivir for Treatment of SARS-CoV-2 in Vitro ', Antimicrobial Agents and Chemotherapy, vol. 65, no. 9, e02680-20 . https://doi.org/10.1128/AAC.02680-20 |
| ISSN: | 1098-6596 |
| Popis: | Antivirals targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could improve treatment of COVID-19. We evaluated the efficacy of clinically relevant hepatitis C virus (HCV) NS3 protease inhibitors (PIs) against SARS-CoV-2 and their interactions with remdesivir, the only direct-acting antiviral approved for COVID-19 treatment. HCV PIs showed differential potency in short-term treatment assays based on the detection of SARS-CoV-2 spike protein in Vero E6 cells. Linear PIs boceprevir, telaprevir, and narlaprevir had 50% effective concentrations (EC50) of ∼40 μM. Among the macrocyclic PIs, simeprevir had the highest (EC50, 15 μM) and glecaprevir the lowest (EC50, >178 μM) potency, with paritaprevir, grazoprevir, voxilaprevir, vaniprevir, danoprevir, and deldeprevir in between. Acyclic PIs asunaprevir and faldaprevir had EC50s of 72 and 23 μM, respectively. ACH-806, inhibiting the HCV NS4A protease cofactor, had an EC50 of 46 μM. Similar and slightly increased PI potencies were found in human hepatoma Huh7.5 cells and human lung carcinoma A549-hACE2 cells, respectively. Selectivity indexes based on antiviral and cell viability assays were highest for linear PIs. In short-term treatments, combination of macrocyclic but not linear PIs with remdesivir showed synergism in Vero E6 and A549-hACE2 cells. Longer-term treatment of infected Vero E6 and A549-hACE2 cells with 1-fold EC50 PI revealed minor differences in the barrier to SARS-CoV-2 escape. Viral suppression was achieved with 3- to 8-fold EC50 boceprevir or 1-fold EC50 simeprevir or grazoprevir, but not boceprevir, in combination with 0.4- to 0.8-fold EC50 remdesivir; these concentrations did not lead to viral suppression in single treatments. This study could inform the development and application of protease inhibitors for optimized antiviral treatments of COVID-19. |
| Databáze: | OpenAIRE |
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