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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 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.
Highlights
BK polyomavirus (BKV), known as human polyomavirus 1, is a small non-enveloped virus with a circular double-stranded DNA genome
In order to better characterize the structural relationship between the BKV major structural protein VP1 and the minor capsid proteins VP2 and VP3, we focused on a stretch of amino acids near the carboxyl-terminus of VP2/3 previously referenced as ‘D1’ (Nakanishi et al, 2006)
Polyomaviruses are the causative agents of multiple human diseases, and the lack of effective antiviral therapeutics for the treatment of polyomavirus infections and associated diseases represent an unmet medical need
Summary
BK polyomavirus (BKV), known as human polyomavirus 1, is a small non-enveloped virus with a circular double-stranded DNA genome. BKV was first isolated from an immunosuppressed kidney transplant recipient in 1971 (Gardner et al, 1971), and is among the few clinically important human polyomaviruses, including JC polyomavirus (JCV) (Padgett et al, 1971) and Merkel cell polyomavirus (Feng et al, 2008). BKV is ubiquitous in human populations, with an estimated ~80% sero-prevalence worldwide (Kean et al, 2009; Knowles, 2006). Primary exposure to BKV occurs in early childhood, with 50% of 3-year-olds and over 90% of 10-year-olds testing sero-positive (Knowles, 2001). Reactivation of BKV infection can occur in conditions of immunosuppression, in the context of kidney and hematopoietic cell transplantation. BKV reactivation in allogeneic hematopoietic cell transplant recipients can result in hemorrhagic cystitis (HC).
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