Novel Mutations in NSP1 and PLPro of SARS-CoV-2 NIB-1 Genome Mount for Effective Therapeutics

Hossain, M. U.; Bhattacharjee, A.; Hossain Emon, M. T.; Chowdhury, Z. M.; Mosaib, M. G.; Moniruzzaman, M.; Rahman, M. H.; Islam, M. N.; Ahmed, I.; Amin, M. R.; Rashed, A.; Das, K. C.; Keya, C. A.; Salimullah, M.

doi:10.1101/2020.12.02.408229

bioRxiv · 10.1101/2020.12.02.408229

Novel Mutations in NSP1 and PLPro of SARS-CoV-2 NIB-1 Genome Mount for Effective Therapeutics

Hossain, M. U.·Bhattacharjee, A.·Hossain Emon, M. T.·Chowdhury, Z. M.·Mosaib, M. G.·Moniruzzaman, M.·Rahman, M. H.·Islam, M. N.·Ahmed, I.·Amin, M. R.·Rashed, A.·Das, K. C.·Keya, C. A.·Salimullah, M.

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Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of Coronavirus Disease-2019 (COVID-19), is rapidly accumulating new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Recently, we have reported a Sanger method based genome sequence of a viral isolate named SARS-CoV-2 NIB-1, circulating in Bangladesh. The genome has four novel mutations in V121D, V843F, A889V and G1691C positions. V121D substitution has the potential to destabilize the Non-Structural Protein (NSP-1) which inactivates the type-1 Interferon-induced antiviral system hence this mutant could be the basis of attenuated vaccines against SARS-CoV-V843F, A889V and G1691C are all located in NSP3. G1691C can decrease the flexibility of the protein while V843F and A889V changed the binding pattern of SARS-CoV-2 Papain-Like protease (PLPro) inhibitor GRL0617. V843F PLPro showed reduced affinity for Interferon Stimulating Gene-15 (ISG-15) protein whereas V843F+A889V double mutants exhibited the same binding affinity as wild type PLPro. Here, V843F is a conserved position of PLPro that damaged the structure but A889V, a less conserved residue, most probably neutralized that damage. Mutants of NSP1 could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro could be targeted to develop anti-SARS therapeutics.

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Hossain, M. U., Bhattacharjee, A., Hossain Emon, M. T., Chowdhury, Z. M., Mosaib, M. G., Moniruzzaman, M., Rahman, M. H., Islam, M. N., Ahmed, I., Amin, M. R., Rashed, A., Das, K. C., Keya, C. A., Salimullah, M.. 2020-12-02. Novel Mutations in NSP1 and PLPro of SARS-CoV-2 NIB-1 Genome Mount for Effective Therapeutics. https://doi.org/10.1101/2020.12.02.408229

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