Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease.

Stevaert, Annelies; Krasniqi, Besir; Van Loy, Benjamin; Nguyen, Tien; Thomas, Joice; Vandeput, Julie; Jochmans, Dirk; Thiel, Volker; Dijkman, Ronald; Dehaen, Wim; Voet, Arnout; Naesens, Lieve (2021). Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease. Journal of medicinal chemistry, 64(9), pp. 5632-5644. American Chemical Society 10.1021/acs.jmedchem.0c02124

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Thiel, Volker Earl and Dijkman, Ronald

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0022-2623

Publisher:

American Chemical Society

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

13 Jul 2021 09:19

Last Modified:

13 Jul 2021 09:19

Publisher DOI:

10.1021/acs.jmedchem.0c02124

PubMed ID:

33877845

BORIS DOI:

10.48350/156609

URI:

https://boris.unibe.ch/id/eprint/156609

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