A polyomavirus peptide binds to the capsid VP1 pore and has potent antiviral activity against BK and JC polyomaviruses.

Autor: Kane JR; Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States.; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States., Fong S; Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States., Shaul J; Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Emeryville, United States., Frommlet A; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States., Frank AO; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States., Knapp M; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States., Bussiere DE; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States., Kim P; Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States., Ornelas E; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States., Cuellar C; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States., Hyrina A; Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Emeryville, United States., Abend JR; Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States., Wartchow CA; Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States.
Jazyk: angličtina
Zdroj: ELife [Elife] 2020 Jan 21; Vol. 9. Date of Electronic Publication: 2020 Jan 21.
DOI: 10.7554/eLife.50722
Abstrakt: In pursuit of therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen-residue peptide binds to major structural protein VP1 with single-digit nanomolar affinity. Alanine-scanning of the peptide identified three key residues, substitution of each of which results in ~1000 fold loss of binding affinity with a concomitant reduction in antiviral activity. Structural studies demonstrate specific binding of the peptide to the pore of pentameric VP1. Cell-based assays demonstrate nanomolar inhibition (EC 50 ) of BKV infection and suggest that the peptide acts early in the viral entry pathway. Homologous peptide exhibits similar binding to JC polyomavirus VP1 and inhibits infection with similar potency to BKV in a model cell line. Lastly, these studies validate targeting the VP1 pore as a novel strategy for the development of anti-polyomavirus agents.
Competing Interests: JK, SF, JS, AF, AF, MK, DB, PK, EO, CC, AH, JA, CW was employed by the Novartis Institutes for BioMedical Research while this work was conducted
(© 2020, Kane et al.)
Databáze: MEDLINE
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