Peptide inhibitors derived from the nsp7 and nsp8 cofactors of nsp12 targeting different substrate binding sites of nsp12 of the SARS-CoV-2

Abstract

SARS-COV-2 is responsible for the COVID-19 pandemic, which has infected more than 767 million people worldwide including about 7 million deaths till 5 June 2023. Despite the emergency use of certain vaccines, deaths due to COVID-19 have not yet stopped completed. Therefore, it is imperative to design and develop drugs that can be used to treat patients suffering from COVID-19. Here, two peptide inhibitors derived from nsp7 and nsp8 cofactors of nsp12 have been shown to block different substrate binding sites of nsp12 that are mainly responsible for the replication of the viral genome of SARS-CoV-2. By using the docking, molecular dynamics (MD), and MM/GBSA techniques, it is shown that these inhibitors can bind to multiple binding sites of nsp12, such as the interface of nsp7 and nsp12, interface of nsp8 and nsp12, RNA primer entry site, and nucleoside triphosphate (NTP) entry site. The relative binding free energies of the most stable protein-peptide complexes are found to lie between ∼−34.20 ± 10.07 to −59.54 ± 9.96 kcal/mol. Hence, it is likely that these inhibitors may bind to different sites of nsp12 to block the access of its cofactors and the viral genome, thereby affecting the replication. It is thus proposed that these peptide inhibitors may be further developed as potential drug candidates to suppress the viral loads in COVID-19 patients.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-COV-2
• COVID-19
• peptide inhibitors
• RdRp
• MD-simulations

Acknowledgments

NRJ is thankful to the Science and Engineering Research Board (SERB, New Delhi) and the Council of Scientific and Industrial Research (CSIR, New Delhi) for financial supports. SP is thankful to NIPER, Kolkata, and the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, for providing necessary resources and fellowship.

Author contributions

NRJ conceptualized the work. SP performed simulations. NRJ analyzed the results and provided the necessary guidance. NRJ wrote the paper. NRJ and SP read the paper and approved its publication.

Disclosure statement

No potential conflict of interest was reported by the author(s).