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J Med Chem ; 64(9): 5632-5644, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1193564


To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC50: 0.6 µM) of HCoV-229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of HCoV-229E nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.

Antiviral Agents/pharmacology , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/enzymology , Endoribonucleases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Oleanolic Acid/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cell Line , Dose-Response Relationship, Drug , Endoribonucleases/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Microbial Sensitivity Tests , Models, Molecular , Oleanolic Acid/chemical synthesis , Oleanolic Acid/chemistry , Oleanolic Acid/pharmacology , Viral Nonstructural Proteins/metabolism