About: A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses that Cause SARS and COVID-19

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About: A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses that Cause SARS and COVID-19 Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses that Cause SARS and COVID-19
Creator	Ju, Jingyue Anderson, Thomas Chien, Minchen Jockusch, Steffen Kirchdoerfer, Robert Kumar, Shiv Li, X Li, Xiaoxu Russo, James Tao, Chuanjuan Kumar, S Tao, C Anderson, T Chien, M Jockusch, S Kirchdoerfer, J
Source	Elsevier; Medline; PMC
abstract	SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2’ or 3’ modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. The goal is to identify nucleotide analogues that not only terminate RNA synthesis catalyzed by these coronavirus RdRps, but also have the potential to resist the viruses’ exonuclease activity. We examined these nucleotide analogues for their ability to be incorporated by the RdRps in the polymerase reaction and to prevent further incorporation. While all 11 molecules tested displayed incorporation, 6 exhibited immediate termination of the polymerase reaction (triphosphates of Carbovir, Ganciclovir, Stavudine and Entecavir; 3’-OMe-UTP and Biotin-16-dUTP), 2 showed delayed termination (Cidofovir diphosphate and 2’-OMe-UTP), and 3 did not terminate the polymerase reaction (2’-F-dUTP, 2’-NH(2)-dUTP and Desthiobiotin-16-UTP). The coronaviruses possess an exonuclease that apparently requires a 2’-OH at the 3’-terminus of the growing RNA strand for proofreading. In this study, all nucleoside triphosphate analogues evaluated form Watson-Crick-like base pairs. The nucleotide analogues demonstrating termination either lack a 2’-OH, have a blocked 2’-OH, or show delayed termination. Thus, these nucleotide analogues are of interest for further investigation to evaluate whether they can evade the viral exonuclease activity. Prodrugs of five of these nucleotide analogues (Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine and Entecavir) are FDA-approved medications for treatment of other viral infections, and their safety profiles are well established. After demonstrating potency in inhibiting viral replication in cell culture, candidate molecules can be rapidly evaluated as potential therapies for COVID-19.
has issue date	2020-06-18(xsd:dateTime)
bibo:doi	10.1016/j.antiviral.2020.104857
bibo:pmid	32562705
has license	no-cc
sha1sum (hex)	410637a55b04f3e9bd5b71701ab9d4c040a088ca
schema:url	https://doi.org/10.1016/j.antiviral.2020.104857
resource representing a document's title	A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses that Cause SARS and COVID-19
has PubMed Central identifier	PMC7299870
has PubMed identifier	32562705
schema:publication	Antiviral Res
resource representing a document's body	covid:410637a55b04f3e9bd5b71701ab9d4c040a088ca#body_text
is schema:about of	named entity 'SARS-CoV-2' named entity 'demonstrated' named entity 'Emtricitabine' named entity 'acyclic' named entity 'carbocyclic' named entity 'genome' named entity 'family' named entity 'medications' named entity 'analogues' named entity 'dideoxynucleotides' named entity 'SARS-CoV' named entity 'base pairs' named entity 'Nucleotide' named entity 'RNA' named entity 'DIPHOSPHATE' named entity 'VALGANCICLOVIR' named entity 'NUCLEOSIDE TRIPHOSPHATE ANALOGUES' named entity 'EXAMINED' named entity 'DESTHIOBIOTIN' named entity 'activity' named entity 'RNA' named entity 'member' named entity 'Abacavir' named entity 'terminate' named entity 'potential' named entity 'catalyzed' named entity 'therapies' named entity 'nucleotide analogues' named entity 'nucleotide analogues' named entity 'nucleotide analogue' named entity 'smallpox' named entity 'exonuclease activity' named entity 'RNA' named entity 'polymerase' named entity 'oral drug' named entity 'ATP' named entity 'ATP' named entity 'Biotin' named entity 'CMV' named entity 'herpesviruses' named entity 'polymerase' named entity 'diphosphate' named entity 'SARS-CoV' named entity 'pre-exposure prophylaxis' named entity 'ATP' named entity 'exonuclease' named entity 'RNA-dependent RNA polymerase' named entity 'Entecavir' named entity 'annealed' named entity 'ProTide' named entity 'ATP' named entity 'SARS-CoV-2' named entity 'prodrug' named entity 'd4T' named entity 'MALDI-TOF-MS' named entity 'uridine' named entity 'potency' named entity 'ester' named entity 'SARS-CoV' named entity 'Biotin' named entity 'toxicity' named entity 'Biotin' named entity 'Stavudine' named entity 'genome' named entity 'prodrug' named entity 'diphosphate'

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