Issue 44, 2023

Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

Abstract

Human papillomavirus (HPV) infections account for nearly all cervical cancer cases, which is the fourth most common cancer in women worldwide. High-risk variants, including HPV16, drive tumorigenesis in part by promoting the degradation of the tumor suppressor p53. This degradation is mediated by the HPV early protein 6 (E6), which recruits the E3 ubiquitin ligase E6AP and redirects its activity towards ubiquitinating p53. Targeting the protein interaction interface between HPV E6 and E6AP is a promising modality to mitigate HPV-mediated degradation of p53. In this study, we designed a covalent peptide inhibitor, termed reactide, that mimics the E6AP LXXLL binding motif by selectively targeting cysteine 58 in HPV16 E6 with quantitative conversion. This reactide provides a starting point in the development of covalent peptidomimetic inhibitors for intervention against HPV-driven cancers.

Graphical abstract: Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

Supplementary files

Article information

Article type
Edge Article
Submitted
01 Jūn. 2023
Accepted
22 Aug. 2023
First published
25 Okt. 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 12484-12497

Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

X. Ye, P. Zhang, J. Tao, J. C. K. Wang, A. Mafi, N. M. Grob, A. J. Quartararo, H. T. Baddock, L. J. G. Chan, F. E. McAllister, I. Foe, A. Loas, D. L. Eaton, Q. Hao, A. H. Nile and B. L. Pentelute, Chem. Sci., 2023, 14, 12484 DOI: 10.1039/D3SC02782A

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