About: Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase

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About: Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase Goto Sponge NotDistinct Permalink

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase
Creator	Canard, Bruno Decroly, Etienne Debart, Françoise Vasseur, Jean-Jacques Sutto-Ortiz, Priscila Ahmed-Belkacem, Rostom Guiraud, Mathis
source	Elsevier; Medline; PMC
abstract	The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7- or 2’O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2’-O-methylation of the cap RNA in order to block viral 2’-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2’-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase.
has issue date	2020-06-12(xsd:dateTime)
bibo:doi	10.1016/j.ejmech.2020.112557
bibo:pmid	32563813
has license	no-cc
sha1sum (hex)	16d9e80a306594d9b3909f51ce4e7a742ee29d95
schema:url	https://doi.org/10.1016/j.ejmech.2020.112557
resource representing a document's title	Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase
has PubMed Central identifier	PMC7291971
has PubMed identifier	32563813
schema:publication	Eur J Med Chem
resource representing a document's body	covid:16d9e80a306594d9b3909f51ce4e7a742ee29d95#body_text
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