Synthesis of Adenine Dinucleosides 2′,5′-Bridged by Sulfur-Containing Linkers as Bisubstrate SAM Analogues for Viral RNA 2′- O -Methyltransferases

Rostom Ahmed-Belkacem (1) , Priscila Sutto Ortiz (2) , Etienne Decroly (2) , Jean-Jacques Vasseur (1) , Françoise Debart (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 AFMB - Architecture et fonction des macromolécules biologiques

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.

Mots clés: Bisubstrate; RNA 2 '-O-methylation; Transition states; Viral RNA methyltransferases; Nucleosides

Domaines: Chimie; Chimie organique

Rostom Ahmed-Belkacem, Priscila Sutto Ortiz, Etienne Decroly, Jean-Jacques Vasseur, Françoise Debart. Synthesis of Adenine Dinucleosides 2′,5′-Bridged by Sulfur-Containing Linkers as Bisubstrate SAM Analogues for Viral RNA 2′- O -Methyltransferases. European Journal of Organic Chemistry, 2019, 2019 (38), ⟨10.1002/ejoc.201901120⟩. ⟨hal-02992283⟩