Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

Xiyun Ye, Peiyuan Zhang, Jason Tao, John C. K. Wang, Amirhossein Mafi, Nathalie M. Grob, Anthony J. Quartararo, Hannah T. Baddock, Leanne J. G. Chan, Fiona E. McAllister, Ian Foe, Andrei Loas, Dan L. Eaton, Qi Hao, Aaron H. Nile and Bradley L. Pentelute

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.

Category
2023, Publications