tetano
Editor, Senior Moderator
Cell Host Microbe
. 2022 Aug 11;S1931-3128(22)00402-4.
doi: 10.1016/j.chom.2022.08.003. Online ahead of print.
Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites
Sho Iketani[SUP] 1 [/SUP], Seo Jung Hong[SUP] 2 [/SUP], Jenny Sheng[SUP] 3 [/SUP], Farideh Bahari[SUP] 4 [/SUP], Bruce Culbertson[SUP] 5 [/SUP], Fereshteh Fallah Atanaki[SUP] 4 [/SUP], Arjun K Aditham[SUP] 6 [/SUP], Alexander F Kratz[SUP] 3 [/SUP], Maria I Luck[SUP] 7 [/SUP], Ruxiao Tian[SUP] 8 [/SUP], Stephen P Goff[SUP] 9 [/SUP], Hesam Montazeri[SUP] 4 [/SUP], Yosef Sabo[SUP] 7 [/SUP], David D Ho[SUP] 10 [/SUP], Alejandro Chavez[SUP] 11 [/SUP]
Affiliations
Abstract
The SARS-CoV-2 3CL protease (3CL[SUP]pro[/SUP]) is an attractive therapeutic target, as it is essential to the virus and highly conserved among coronaviruses. However, our current understanding of its tolerance to mutations is limited. Here, we develop a yeast-based deep mutational scanning approach to systematically profile the activity of all possible single mutants of the 3CL[SUP]pro[/SUP] and validate a subset of our results within authentic viruses. We reveal that the 3CL[SUP]pro[/SUP] is highly malleable and is capable of tolerating mutations throughout the protein. Yet, we also identify specific residues that appear immutable, suggesting that these may be targets for future 3CL[SUP]pro[/SUP] inhibitors. Finally, we utilize our screening as a basis to identify E166V as a resistance-conferring mutation against the clinically used 3CL[SUP]pro[/SUP] inhibitor, nirmatrelvir. Collectively, the functional map presented herein may serve as a guide to better understand the biological properties of the 3CL[SUP]pro[/SUP] and for drug development against coronaviruses.
Keywords: 3CL protease; COVID-19; SARS-CoV-2; deep mutational scanning; drug resistance; nirmatrelvir; protease inhibitors.
. 2022 Aug 11;S1931-3128(22)00402-4.
doi: 10.1016/j.chom.2022.08.003. Online ahead of print.
Functional map of SARS-CoV-2 3CL protease reveals tolerant and immutable sites
Sho Iketani[SUP] 1 [/SUP], Seo Jung Hong[SUP] 2 [/SUP], Jenny Sheng[SUP] 3 [/SUP], Farideh Bahari[SUP] 4 [/SUP], Bruce Culbertson[SUP] 5 [/SUP], Fereshteh Fallah Atanaki[SUP] 4 [/SUP], Arjun K Aditham[SUP] 6 [/SUP], Alexander F Kratz[SUP] 3 [/SUP], Maria I Luck[SUP] 7 [/SUP], Ruxiao Tian[SUP] 8 [/SUP], Stephen P Goff[SUP] 9 [/SUP], Hesam Montazeri[SUP] 4 [/SUP], Yosef Sabo[SUP] 7 [/SUP], David D Ho[SUP] 10 [/SUP], Alejandro Chavez[SUP] 11 [/SUP]
Affiliations
- PMID: 36029764
- DOI: 10.1016/j.chom.2022.08.003
Abstract
The SARS-CoV-2 3CL protease (3CL[SUP]pro[/SUP]) is an attractive therapeutic target, as it is essential to the virus and highly conserved among coronaviruses. However, our current understanding of its tolerance to mutations is limited. Here, we develop a yeast-based deep mutational scanning approach to systematically profile the activity of all possible single mutants of the 3CL[SUP]pro[/SUP] and validate a subset of our results within authentic viruses. We reveal that the 3CL[SUP]pro[/SUP] is highly malleable and is capable of tolerating mutations throughout the protein. Yet, we also identify specific residues that appear immutable, suggesting that these may be targets for future 3CL[SUP]pro[/SUP] inhibitors. Finally, we utilize our screening as a basis to identify E166V as a resistance-conferring mutation against the clinically used 3CL[SUP]pro[/SUP] inhibitor, nirmatrelvir. Collectively, the functional map presented herein may serve as a guide to better understand the biological properties of the 3CL[SUP]pro[/SUP] and for drug development against coronaviruses.
Keywords: 3CL protease; COVID-19; SARS-CoV-2; deep mutational scanning; drug resistance; nirmatrelvir; protease inhibitors.