PEX14 inhibitors(Helmholtz Zentrum München)

Nsp14 is an RNA methyltransferase (MTase) encoded by all coronaviruses.In fact, many viral families, including DNA viruses, encode MTases that catalyze the methylation of the RNA precap structure, resulting in fully capped viral RNA.This capping is crucial for efficient viral RNA translation, stability, and immune evasion.Our previous research identified nsp14 inhibitors based on the chem. scaffold of its Me donor - the S-adenosyl methionine (SAM) - featuring a modified adenine base and a substituted arylsulfonamide.However, the binding mode of these inhibitors was based only on docking experimentsTo uncover at. details of nsp14 inhibition we solved the crystal structure of nsp14 bound to STM957.The structure revealed the at. details of nsp14 inhibition such that the 7-deaza-adenine moiety of STM957 forms specific interactions with Tyr368, Ala353, and Phe367, while the arylsulfonamide moiety engages with Asn388 and Phe506.The large aromatic substituent at the 7-deaza position displaces a network of water mols. near the adenine base.Surprisingly, this was recently observed in the case of an unrelated monkeypox MTase VP39, where the 7-deaza modified SAH analogs also displaced water mols. from the vicinity of the active site.