Pandemic COVID-19 outbreak has been caused due to SARS-COV2 pathogen, resulting millions of infection and death worldwide, USA being on top at the present moment. The long, complex orf1ab polyproteins of SARS-COV2 play an important role in viral RNA synthesis. To assess the impact of mutations in this important domain, we analyzed 1134 complete protein sequences of orf1ab polyprotein from NCBI Virus database from affected patients across various states of USA from December 2019 to 25 th April, 2020. Multiple sequence alignment using Clustal Omega followed by statistical significance was calculated. Four significant mutations T265I (nsp 2), P4715L (nsp 12) and P5828L and Y5865C (both at nsp 13) were identified in important non-structural proteins, which function either as replicase or helicase. A comparative analysis shows 265T>I, 5828P>L and 5865Y>C are unique to USA and not reported from Europe or Asia; while one, 4715P>L is predominant in both Europe and USA. Mutational changes in amino acids are predicted to alter structure and function of corresponding proteins, thereby it is imperative to consider the mutational spectra while designing new antiviral therapeutics targeting viral orf1ab.

Pandemic COVID‐19 outbreak has been caused due to SARS‐CoV‐2 pathogen, resulting millions of infection and death worldwide, USA being on top at the present moment. The long, complex orf1ab polyproteins of SARS‐CoV‐2 play an important role in viral RNA synthesis. To assess the impact of mutations in this important domain, we analyzed 1134 complete protein sequences of orf1ab polyprotein from NCBI Virus database from affected patients across various states of USA from December 2019 to 25 th April 2020. Multiple sequence alignment using Clustal Omega followed by statistical significance was calculated. Four significant mutations T265I (nsp 2), P4715L (nsp 12) and P5828L and Y5865C (both at nsp 13) were identified in important non‐structural proteins, which function either as replicase or helicase. A comparative analysis shows 265T→I, 5828P→L and 5865Y→C are unique to USA and not reported from Europe or Asia; while one, 4715P→L is predominant in both Europe and USA. Mutational changes in amino acids are predicted to alter structure and function of corresponding proteins, thereby it is imperative to consider the mutational spectra while designing new antiviral therapeutics targeting viral orf1ab. This article is protected by copyright. All rights reserved.

Background and Objective: COVID-19 originated in Wuhan, China and expanded to different geographical location of the world with variation in its sequence due to mutation, consequent alteration in different protein structures; resulting in different interaction with the host body. The highly infectious and diverge character of the virus makes it imperative to identify the promising inhibitory compounds for RdRp, 3CLpro and PLpro as suitable antiviral drug target so that viral duplication can be prevented in the host body.Methods: RdRp, 3CLpro and PLpro sequences of Indian patients were retrieved from the database and MSA was employed to identify mutation at nsp 3, nsp 5 and nsp 12. Protein structures were modeled considering all possible combination of sequences abundant in India and docking was performed with repurposed drugs, currently under trial for COVID-19, using Autodock Vina to find out the suitable ones considering the mutational spectra of SARS-CoV-2 in India.Results: PLpro is found to be most vulnerable to mutations with four mutations found in >5% studied population whereas in 3CLpro none observed at the frequency > 5%, so far. Two mutations were reported among Indian population (>5%) at RdRp. Therefore 3CLpro and RdRp were further analysed as a suitable target for repurposed drugs. Elbasvir has come up as the most suitable drug to inhibit the activity of RdRp in Indian population, followed by Remdesivir and Methylprednisolone. TMC 310911, Lopinavir and Elbasvir again, found to be the best candidates for inhibiting 3CLpro.Interpretation and Conclusions: Remdesivir and Lopinavir(alone or in combination with Ritonavir), the most popular drugs of choice at recent times may be suitable to be used in Indian population, considering the mutational variations in Indian population. Among others, Elbasvir, TMC 310911 and Methylprednisolone are good choices for treating COVID-19.

Pandemic COVID-19 outbreak has been caused due to SARS-COV2 pathogen, resulting millions of infection and death worldwide, USA being on top at the present moment. The long, complex orf1ab polyproteins of SARS-COV2 play an important role in viral RNA synthesis. To assess the impact of mutations in this important domain, we analyzed 1134 complete protein sequences of orf1ab polyprotein from NCBI Virus database from affected patients across various states of USA from December 2019 to 25 th April, 2020. Multiple sequence alignment using Clustal Omega followed by statistical significance was calculated. Four significant mutations T265I (nsp 2), P4715L (nsp 12) and P5828L and Y5865C (both at nsp 13) were identified in important non-structural proteins, which function either as replicase or helicase. A comparative analysis shows 265T>I, 5828P>L and 5865Y>C are unique to USA and not reported from Europe or Asia; while one, 4715P>L is predominant in both Europe and USA. Mutational changes in amino acids are predicted to alter structure and function of corresponding proteins, thereby it is imperative to consider the mutational spectra while designing new antiviral therapeutics targeting viral orf1ab.