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Letter
Identification of Mutation Resistance Coldspots for Targeting the SARS-CoV2 Main Protease
Navaneethakrishnan Krishnamoorthy
Sidra Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5096-4612
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Most attempts to target the novel coronavirus SARS-CoV2 are focusing on the main protease (Mpro) 1-9. However, >19,000 mutations in the Mpro have already been reported 10. The mutations encompassing 282 amino acid positions and these “hotspots” might change the Mpro structure and activity, potentially rendering novel antivirals and vaccines ineffective. Here we identified 24 mutational “coldspots” that have resisted mutation since the virus was first detected. We compared the structure-function relationship of these coldspots with several SARS-CoV2 Mpro X-ray crystal structures. We found that three coldspot residues (Leu141, Phe185 and Gln192) help to form the active site, while six (Gly2, Arg4, Tyr126, Lys137, Leu141 and Leu286) contribute to dimer formation that is required for Mpro activity. The surface of the dimer interface is more resistant to mutations compared to the active site. Interestingly, 16 coldspots are found in conserved patterns when compared with other coronaviruses. Importantly, several conserved coldpots are available on the surface of the active site and at the dimer interface for targeting. The identification and short list of these coldspots offers a new perspective to target the SARS-CoV2 Mpro while avoiding mutation-based drug resistance.
Keywords
Mutation Hotspot, X-ray Structure, Missense Mutation, Structure-function Relationship, Dimer interface, Mutation-based Drug Resistance, Surface coldspots
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Supplementary data set Table1
Dr N Prabha
commented on 02 January, 2021
Interesting and helpful advice for the vaccine
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This is a preprint. It has not completed peer review.
Letter
Identification of Mutation Resistance Coldspots for Targeting the SARS-CoV2 Main Protease
Navaneethakrishnan Krishnamoorthy
Sidra Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5096-4612
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 3
Posted 28 Dec, 2020
Community comments: 1
No comments provided
No comments provided
Metrics
Comments: 1
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Most attempts to target the novel coronavirus SARS-CoV2 are focusing on the main protease (Mpro) 1-9. However, >19,000 mutations in the Mpro have already been reported 10. The mutations encompassing 282 amino acid positions and these “hotspots” might change the Mpro structure and activity, potentially rendering novel antivirals and vaccines ineffective. Here we identified 24 mutational “coldspots” that have resisted mutation since the virus was first detected. We compared the structure-function relationship of these coldspots with several SARS-CoV2 Mpro X-ray crystal structures. We found that three coldspot residues (Leu141, Phe185 and Gln192) help to form the active site, while six (Gly2, Arg4, Tyr126, Lys137, Leu141 and Leu286) contribute to dimer formation that is required for Mpro activity. The surface of the dimer interface is more resistant to mutations compared to the active site. Interestingly, 16 coldspots are found in conserved patterns when compared with other coronaviruses. Importantly, several conserved coldpots are available on the surface of the active site and at the dimer interface for targeting. The identification and short list of these coldspots offers a new perspective to target the SARS-CoV2 Mpro while avoiding mutation-based drug resistance.
Figure 1
Figure 2
Figure 3
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the latest manuscript can be downloaded and accessed as a PDF.
Dr N Prabha
commented on 02 January, 2021
Interesting and helpful advice for the vaccine