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Identifying Structural Features of Nucleotide Analogues to Overcome SARS-CoV-2 Exonuclease Activity.
Wang, Xuanting; Tao, Chuanjuan; Morozova, Irina; Kalachikov, Sergey; Li, Xiaoxu; Kumar, Shiv; Russo, James J; Ju, Jingyue.
  • Wang X; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.
  • Tao C; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.
  • Morozova I; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.
  • Kalachikov S; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.
  • Li X; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.
  • Kumar S; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.
  • Russo JJ; Center for Genome Technology and Biomolecular Engineering, Columbia University, New York, NY 10027, USA.
  • Ju J; Department of Chemical Engineering, Columbia University, New York, NY 10027, USA.
Viruses ; 14(7)2022 06 28.
Article in English | MEDLINE | ID: covidwho-1911662
ABSTRACT
With the recent global spread of new SARS-CoV-2 variants, there remains an urgent need to develop effective and variant-resistant oral drugs. Recently, we reported in vitro results validating the use of combination drugs targeting both the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and proofreading exonuclease (ExoN) as potential COVID-19 therapeutics. For the nucleotide analogues to be efficient SARS-CoV-2 inhibitors, two properties are required efficient incorporation by RdRp and substantial resistance to excision by ExoN. Here, we have selected and evaluated nucleotide analogues with a variety of structural features for resistance to ExoN removal when they are attached at the 3' RNA terminus. We found that dideoxynucleotides and other nucleotides lacking both 2'- and 3'-OH groups were most resistant to ExoN excision, whereas those possessing both 2'- and 3'-OH groups were efficiently removed. We also found that the 3'-OH group in the nucleotide analogues was more critical than the 2'-OH for excision by ExoN. Since the functionally important sequences in Nsp14/10 are highly conserved among all SARS-CoV-2 variants, these identified structural features of nucleotide analogues offer invaluable insights for designing effective RdRp inhibitors that can be simultaneously efficiently incorporated by the RdRp and substantially resist ExoN excision. Such newly developed RdRp terminators would be good candidates to evaluate their ability to inhibit SARS-CoV-2 in cell culture and animal models, perhaps combined with additional exonuclease inhibitors to increase their overall effectiveness.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Topics: Variants Limits: Animals Language: English Year: 2022 Document Type: Article Affiliation country: V14071413

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Topics: Variants Limits: Animals Language: English Year: 2022 Document Type: Article Affiliation country: V14071413