SARS-CoV-2 RdRp uses NDPs as a substrate and is able to incorporate NHC into RNA from diphosphate form molnupiravir

• Published in: bioRxiv 2022-04
• Main Authors: Wang, Maofeng, Wu, Cancan, Liu, Nan, Zhang, Fengyu, Dong, Hongjie, Wang, Shuai, Chen, Min, Jiang, Xiaoqiong, Gu, Lichuan
• Format: Article
• Language: English
• Subjects: Coronaviruses; COVID-19; DNA-directed RNA polymerase; Drug development; Genomes; Molecular Biology; Nucleoside triphosphates; RNA polymerase; RNA-directed RNA polymerase; Severe acute respiratory syndrome coronavirus 2; Transcription
• ISSN: 2692-8205
• DOI: 10.1101/2021.11.15.468737

The coronavirus disease 2019 (COVID-19) has been ravaging throughout the world for more than two years and has severely impaired both human health and the economy. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) employs the viral RNA-dependent RNA polymerase (RdRp) complex for genome replication and transcription, making RdRp an appealing target for antiviral drug development. Here, we reveal that RdRp can recognize and utilize nucleoside diphosphates (NDPs) as a substrate to synthesize RNAs with an efficiency of about two thirds of using nucleoside triphosphates (NTPs) as a substrate. NDPs incorporation is also template-specific and has high fidelity. Moreover, RdRp can incorporate β-d-N4-hydroxycytidine (NHC) into RNA while using diphosphate form molnupiravir (MDP) as a substrate. We also observed that MDP is a better substrate for RdRp than the triphosphate form molnupiravir (MTP). Competing Interest Statement The authors have declared no competing interest.