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bioRxiv · 10.1101/2022.03.12.484092

Discovery of anti-SARS-CoV-2 molecules using structure-assisted repurposing approach targeting N-protein

Dhaka, P.·Singh, A.·Choudhary, S.·Kumar, P.·Sharma, G. K.·Tomar, S.
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Abstract

The N-terminal (NTD) and the C-terminal (CTD) domains comprises the structure of the SARS-CoV-2 Nucleocapsid (N) protein. Crystal structure of the SARS-CoV-2 N protein determined by Kang et al, 2020, reveals the N-terminal RNA binding domain as a unique drug binding site. The present study targets this unique pocket with identified antivirals using structure-based drug repurposing approach. The high-affinity binding of potential molecules was characterised thermodynamically using Isothermal titration calorimetry. The selected molecules showed an inhibitory RNA binding potential between 8.8 M and 15.7 M IC50 when evaluated with a fluorescent-based assay. Furthermore, in an in vitro cell-based antiviral assay, these ten antiviral molecules demonstrated high effectiveness in halting SARS-CoV-2 replication. Telmisartan and BMS-189453, the two highly potent antivirals, have [~]0.98M and 1.02 M EC50 values with the selective index of >102, and >98, respectively. For the first time, this study presents drug molecules specifically targeting the NTD of SARS-CoV-2, offering essential insights for the development of therapeutic interventions against this virus, which is still a potential global threat to public health.

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Dhaka, P., Singh, A., Choudhary, S., Kumar, P., Sharma, G. K., Tomar, S.. 2022-03-14. Discovery of anti-SARS-CoV-2 molecules using structure-assisted repurposing approach targeting N-protein. https://doi.org/10.1101/2022.03.12.484092

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