tetano
Editor, Senior Moderator
Int J Biol Macromol
. 2022 Dec 14;S0141-8130(22)03014-8.
doi: 10.1016/j.ijbiomac.2022.12.112. Online ahead of print.
SARS-CoV-2 RdRp uses NDPs as a substrate and is able to incorporate NHC into RNA from diphosphate form molnupiravir
Maofeng Wang[SUP] 1 [/SUP], Cancan Wu[SUP] 1 [/SUP], Nan Liu[SUP] 1 [/SUP], Fengyu Zhang[SUP] 1 [/SUP], Hongjie Dong[SUP] 1 [/SUP], Shuai Wang[SUP] 1 [/SUP], Min Chen[SUP] 1 [/SUP], Xiaoqiong Jiang[SUP] 1 [/SUP], Kundi Zhang[SUP] 2 [/SUP], Lichuan Gu[SUP] 3 [/SUP]
Affiliations
Abstract
The coronavirus disease 2019 has been ravaging throughout the world for three years and has severely impaired both human health and the economy. The causative agent, severe acute respiratory syndrome coronavirus 2 employs the viral RNA dependent RNA polymerase (RdRp) complex for genome replication and transcription, making RdRp an appealing target for antiviral drug development. Systematic characterization of RdRp will undoubtedly aid in the development of antiviral drugs targeting RdRp. Here, our research reveals that RdRp can recognize and utilize nucleoside diphosphates as a substrate to synthesize RNA with an efficiency of about two thirds of using nucleoside triphosphates as a substrate. Nucleoside diphosphates incorporation is also template-specific and has high fidelity. Moreover, RdRp can incorporate β-d-N4-hydroxycytidine into RNA while using diphosphate form molnupiravir as a substrate. This incorporation results in genome mutation and virus death. It is also observed that diphosphate form molnupiravir is a better substrate for RdRp than the triphosphate form molnupiravir, presenting a new strategy for drug design.
Keywords: Molnupiravir; Nucleoside diphosphate; RNA dependent RNA polymerase; SARS-CoV-2.
. 2022 Dec 14;S0141-8130(22)03014-8.
doi: 10.1016/j.ijbiomac.2022.12.112. Online ahead of print.
SARS-CoV-2 RdRp uses NDPs as a substrate and is able to incorporate NHC into RNA from diphosphate form molnupiravir
Maofeng Wang[SUP] 1 [/SUP], Cancan Wu[SUP] 1 [/SUP], Nan Liu[SUP] 1 [/SUP], Fengyu Zhang[SUP] 1 [/SUP], Hongjie Dong[SUP] 1 [/SUP], Shuai Wang[SUP] 1 [/SUP], Min Chen[SUP] 1 [/SUP], Xiaoqiong Jiang[SUP] 1 [/SUP], Kundi Zhang[SUP] 2 [/SUP], Lichuan Gu[SUP] 3 [/SUP]
Affiliations
- PMID: 36528144
- DOI: 10.1016/j.ijbiomac.2022.12.112
Abstract
The coronavirus disease 2019 has been ravaging throughout the world for three years and has severely impaired both human health and the economy. The causative agent, severe acute respiratory syndrome coronavirus 2 employs the viral RNA dependent RNA polymerase (RdRp) complex for genome replication and transcription, making RdRp an appealing target for antiviral drug development. Systematic characterization of RdRp will undoubtedly aid in the development of antiviral drugs targeting RdRp. Here, our research reveals that RdRp can recognize and utilize nucleoside diphosphates as a substrate to synthesize RNA with an efficiency of about two thirds of using nucleoside triphosphates as a substrate. Nucleoside diphosphates incorporation is also template-specific and has high fidelity. Moreover, RdRp can incorporate β-d-N4-hydroxycytidine into RNA while using diphosphate form molnupiravir as a substrate. This incorporation results in genome mutation and virus death. It is also observed that diphosphate form molnupiravir is a better substrate for RdRp than the triphosphate form molnupiravir, presenting a new strategy for drug design.
Keywords: Molnupiravir; Nucleoside diphosphate; RNA dependent RNA polymerase; SARS-CoV-2.