Wartchow, Charles, Kane, Joshua, Shaul, Jacob, Frank, Andreas, Knapp, Mark, Bussiere, Dirksen, Ornelas, Elizabeth and Hyrina, Anastasia (2020) eLive revised manuscript: A POLYOMAVIRUS PEPTIDE BINDS TO THE CAPSID VP1 PORE AND HAS POTENT ANTIVIRAL ACTIVITY AGAINST BK AND JC POLYOMAVIRUSES. ELife., 9. ISSN 2050-084X

Abstract

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 five-fold pore of pentameric VP1. Cell-based assays demonstrate nanomolar inhibition (EC50) 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.

Item Type:	Article
Keywords:	BKV, JCV, protein-protein interactions, anti-viral, polyomavirus D1min
Date Deposited:	30 Jun 2020 00:45
Last Modified:	30 Jun 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41607