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

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 synthesize 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.