About: Small-Molecule Antiviral β-d-N(4)-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

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About: Small-Molecule Antiviral β-d-N(4)-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Small-Molecule Antiviral β-d-N(4)-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance
Creator	Baric, Ralph Sims, Amy Lu, Xiaotao Sheahan, Timothy Kolykhalov, Alexander Denison, Mark Agostini, Maria Bluemling, Gregory Chappell, James Natchus, Michael Painter, George Pruijssers, Andrea Saindane, Manohar Ac, Sims Andres, Erica El, Andres Ml, Agostini Tp, Sheahan Aa, Kolykhalov Aj, Pruijssers Gr, Bluemling Gribble, Jennifer Lockwood, Mark Ma, Lockwood Mg, Natchus
Source	Medline; PMC
abstract	Coronaviruses (CoVs) have emerged from animal reservoirs to cause severe and lethal disease in humans, but there are currently no FDA-approved antivirals to treat the infections. One class of antiviral compounds, nucleoside analogues, mimics naturally occurring nucleosides to inhibit viral replication. While these compounds have been successful therapeutics for several viral infections, mutagenic nucleoside analogues, such as ribavirin and 5-fluorouracil, have been ineffective at inhibiting CoVs. This has been attributed to the proofreading activity of the viral 3′-5′ exoribonuclease (ExoN). β-d-N(4)-Hydroxycytidine (NHC) (EIDD-1931; Emory Institute for Drug Development) has recently been reported to inhibit multiple viruses. Here, we demonstrate that NHC inhibits both murine hepatitis virus (MHV) (50% effective concentration [EC(50)] = 0.17 μM) and Middle East respiratory syndrome CoV (MERS-CoV) (EC(50) = 0.56 μM) with minimal cytotoxicity. NHC inhibited MHV lacking ExoN proofreading activity similarly to wild-type (WT) MHV, suggesting an ability to evade or overcome ExoN activity. NHC inhibited MHV only when added early during infection, decreased viral specific infectivity, and increased the number and proportion of G:A and C:U transition mutations present after a single infection. Low-level NHC resistance was difficult to achieve and was associated with multiple transition mutations across the genome in both MHV and MERS-CoV. These results point to a virus-mutagenic mechanism of NHC inhibition in CoVs and indicate a high genetic barrier to NHC resistance. Together, the data support further development of NHC for treatment of CoVs and suggest a novel mechanism of NHC interaction with the CoV replication complex that may shed light on critical aspects of replication. IMPORTANCE The emergence of coronaviruses (CoVs) into human populations from animal reservoirs has demonstrated their epidemic capability, pandemic potential, and ability to cause severe disease. However, no antivirals have been approved to treat these infections. Here, we demonstrate the potent antiviral activity of a broad-spectrum ribonucleoside analogue, β-d-N(4)-hydroxycytidine (NHC), against two divergent CoVs. Viral proofreading activity does not markedly impact sensitivity to NHC inhibition, suggesting a novel interaction between a nucleoside analogue inhibitor and the CoV replicase. Further, passage in the presence of NHC generates only low-level resistance, likely due to the accumulation of multiple potentially deleterious transition mutations. Together, these data support a mutagenic mechanism of inhibition by NHC and further support the development of NHC for treatment of CoV infections.
has issue date	2019-11-26(xsd:dateTime)
bibo:doi	10.1128/jvi.01348-19
bibo:pmid	31578288
has license	no-cc
sha1sum (hex)	0dcf0124cf00dbf2e2bf0025fee1bba8a57f81da
schema:url	https://doi.org/10.1128/jvi.01348-19
resource representing a document's title	Small-Molecule Antiviral β-d-N(4)-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance
has PubMed Central identifier	PMC6880162
has PubMed identifier	31578288
schema:publication	J Virol
resource representing a document's body	covid:0dcf0124cf00dbf2e2bf0025fee1bba8a57f81da#body_text
is schema:about of	named entity 'point' named entity 'fluorouracil' named entity 'data' named entity 'mutagenic' named entity 'coronaviruses' named entity 'Drug' named entity 'NHC' named entity 'potential' named entity 'human populations' named entity 'compounds' named entity 'inhibit' named entity 'NHC' named entity 'high' named entity 'nucleosides' named entity 'support' named entity 'infections' named entity 'antivirals' named entity 'treat' named entity 'support' named entity 'presence' named entity 'mechanism' named entity 'potent' named entity 'complex' named entity 'attributed' named entity 'NHC' named entity 'viral' named entity 'inhibited' named entity 'inhibiting' named entity 'analogues' named entity 'ability' named entity 'murine' named entity 'mechanism' named entity 'mutagenic' named entity 'interaction' named entity 'inhibition' named entity 'emerged' named entity 'proofreading' named entity 'Coronavirus' named entity 'antivirals' named entity 'MERS-CoV' named entity 'naturally occurring' named entity 'infection' named entity 'genome' named entity 'transition mutations' named entity 'coronaviruses' named entity 'replicase' named entity 'Middle East respiratory syndrome' named entity '5-fluorouracil' named entity 'wild-type' named entity 'ANTIVIRAL AGENTS' named entity 'Coronavirus' named entity 'VACCINES' named entity 'Proofreading' named entity 'nucleoside' named entity 'MHV' named entity 'Virus' named entity 'ExoN'

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