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

Abstract : Viral RNA 2’-O-methyltransferases play a crucial role for luring the host cell innate antiviral response during a viral infection by catalyzing either the methylation of the 5’-end RNA cap-structure at 2’-OH of nucleoside N1 or by inducing internal 2’-O-methylation of adenosines within RNA sequence using S-adenosyl-L-methionine (SAM) as the methyl donor. Our goal is to synthetized bisubstrate SAM analogues mimicking the transition state of the 2’-O-methylation of the RNA in order to block viral 2’-O-methyltransferases and struggle against emerging viruses. Here we designed and synthesized five dinucleosides by connecting a 5’-thioadenosine representing the SAM to the 2’-OH of another adenosine unit mimicking the RNA substrate, via various sized sulfur-containing linkers such as alkylthioether linkers, sulfoxide or sulfone derivatives, or a disulfide bond.
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https://hal.archives-ouvertes.fr/hal-02890580
Contributor : Etienne Decroly Connect in order to contact the contributor
Submitted on : Friday, November 6, 2020 - 5:26:18 PM
Last modification on : Sunday, June 26, 2022 - 2:55:55 AM
Long-term archiving on: : Sunday, February 7, 2021 - 8:10:28 PM

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Rostom Ahmed-Belkacem, Priscila Sutto-Ortiz, Mathis Guiraud, Bruno Canard, Jean-Jacques Vasseur, et al.. Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase. European Journal of Medicinal Chemistry, Elsevier, 2020, 201, pp.112557. ⟨10.1016/j.ejmech.2020.112557⟩. ⟨hal-02890580⟩

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