Bisubstrate Strategies to Target Methyltransferases

Abstract

Bisubstrate strategies address the lack of specificity encountered with S‐adenosyl‐L‐methionine (SAM) analogues targeting methyltransferases (MTases). Specifically, a bisubstrate inhibitor mimics the transition state complex associating a substrate and the SAM methyl group donor to a particular methyltransferase. These potential inhibitors contain both parts of the substrate and the methyl group donor. In this review, bisubstrate inhibitors of several MTases including DNA, RNA, protein, catechol or nicotinamide MTases are discussed in order to evaluate the interest of these promising molecules for the development of selective therapeutics against cancers, neuropsychiatric disorders and viral infections.

Synthesis of Bisubstrate Analogues for RNA Methylation Studies using two Transition‐Metal‐Catalyzed Reactions

“…These examples show that bisubstrates turn out to be potent molecular tools to explore the active site of RNA MTases [1–13] . Important features must be considered: i) α‐amino acid motif of the cofactor SAM is essential to successfully co‐crystallize bisubstrates in the presence of m 6 A RNA MTases [12] and ii) the nature of the linker impacts the binding efficiency.…”

“…Bisubstrate approach to target methyltransferases (MTases) has been well documented and is considered a promising strategy for the development of selective therapies against cancers, viral infections, and neurological diseases [1] . This strategy has been used for proteins, small molecules, DNA and RNA MTases studies and has been facilitated by the development of methods that enable the synthesis of bisubstrate molecules.…”