Open AccessBetulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease
Author(s) -
Annelies Stevaert,
Besir Krasniqi,
Benjamin Van Loy,
Tien T. Nguyen,
Joice Thomas,
Julie Vandeput,
Dirk Jochmans,
Volker Thiel,
Ronald Dijkman,
Wim Dehaen,
Arnout Voet,
Lieve Naesens
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c02124
Subject(s) - chemistry , endoribonuclease , coronavirus , druggability , viral replication , docking (animal) , virology , virus , biochemistry , biology , rna , covid-19 , infectious disease (medical specialty) , rnase p , gene , medicine , nursing , disease , pathology
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 EC 50 : 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.