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2'- and 3'-Ribose Modifications of Nucleotide Analogues Establish the Structural Basis to Inhibit the Viral Replication of SARS-CoV-2.
Li, Yongfang; Zhang, Dong; Gao, Xin; Wang, Xiaowei; Zhang, Lu.
  • Li Y; State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 350002, Fuzhou, Fujian, China.
  • Zhang D; University of Chinese Academy of Sciences, 100864, Beijing, China.
  • Gao X; State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 350002, Fuzhou, Fujian, China.
  • Wang X; University of Chinese Academy of Sciences, 100864, Beijing, China.
  • Zhang L; Computational Bioscience Research Center (CBRC), Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
J Phys Chem Lett ; 13(18): 4111-4118, 2022 May 12.
Article in English | MEDLINE | ID: covidwho-1829965
ABSTRACT
Inhibition of RNA-dependent RNA polymerase (RdRp) by nucleotide analogues with ribose modification provides a promising antiviral strategy for the treatment of SARS-CoV-2. Previous works have shown that remdesivir carrying 1'-substitution can act as a "delayed chain terminator", while nucleotide analogues with 2'-methyl group substitution could immediately terminate the chain extension. However, how the inhibition can be established by the 3'-ribose modification as well as other 2'-ribose modifications is not fully understood. Herein, we have evaluated the potential of several adenosine analogues with 2'- and/or 3'-modifications as obligate chain terminators by comprehensive structural analysis based on extensive molecular dynamics simulations. Our results suggest that 2'-modification couples with the protein environment to affect the structural stability, while 3'-hydrogen substitution inherently exerts "immediate termination" without compromising the structural stability in the active site. Our study provides an alternative promising modification scheme to orientate the further optimization of obligate terminators for SARS-CoV-2 RdRp.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Journal: J Phys Chem Lett Year: 2022 Document Type: Article Affiliation country: Acs.jpclett.2c00087

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies Limits: Humans Language: English Journal: J Phys Chem Lett Year: 2022 Document Type: Article Affiliation country: Acs.jpclett.2c00087