Rational Design of Stapled Covalent Peptide Modifiers of Oncoprotein E6 from Human Papillomavirus

TL;DR

Scientists designed a new type of peptide that can target and modify the E6 protein from HPV, which is involved in causing cervical cancer.

Contribution

The paper introduces a new class of stapled covalent peptides that specifically target HPV-16 E6 with potential therapeutic applications.

Findings

A stapled peptide was developed to mimic E6AP's LxxLL domain and covalently label a cysteine in HPV-16 E6.

Acrylamide- and haloacetamide-based warheads showed reactivity and specificity for E6 modification.

Structure-based modeling explained warhead reactivity and staple positioning effects on binding affinity.

Abstract

Human Papillomavirus (HPV) is linked to multiple cancers,
most
significantly cervical cancer, for which HPV infection is associated
with nearly all cases. Essential to the oncogenesis of HPV is the
function of the viral protein E6 and its role in degrading the cell
cycle regulator p53. Degradation of p53, and the resultant loss of
cell cycle control, is mediated by E6 recruitment of the E3 ubiquitin
ligase E6AP and subsequent ubiquitination of p53. Here, we report
the design of a stapled peptide that mimics the LxxLL α-helical
domain of E6AP to bind and covalently label a cysteine residue specific
to HPV-16 E6. Several acrylamide- and haloacetamide-based warheads
were evaluated for reactivity and specificity, and a panel of hydrocarbon-stapled
peptides was evaluated for enhanced binding affinity and increased
proteolytic stability. Structure-based modeling was used to rationalize
the observed trends in the reactivity of the warheads and the impact
of the hydrocarbon staple position on the binding affinity of the
stapled peptides. The development of a proteolytically stable and
reactive peptide represents a new class of peptide-based inhibitors
of protein–protein interactions with a potential therapeutic
value toward HPV-derived cancers.

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