Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease.
J Med Chem
; 64(9): 5632-5644, 2021 05 13.
Article
in En
| MEDLINE
| ID: mdl-33877845
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oleanolic Acid
/
Antiviral Agents
/
Virus Replication
/
Viral Nonstructural Proteins
/
Coronavirus 229E, Human
/
Endoribonucleases
/
Enzyme Inhibitors
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2021
Document type:
Article
Affiliation country:
Belgium