2. Academic Validation
  3. Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6

  • Chem Sci. 2023 Oct 25;14(44):12484-12497. doi: 10.1039/d3sc02782a.
Xiyun Ye 1,  Peiyuan Zhang 1,  Jason Tao 1,  John C K Wang 2,  Amirhossein Mafi 2,  Nathalie M Grob 1,  Anthony J Quartararo 1,  Hannah T Baddock 2,  Leanne J G Chan 2,  Fiona E McAllister 2,  Ian Foe 2,  Andrei Loas 1,  Dan L Eaton 2,  Qi Hao 2,  Aaron H Nile 2,  Bradley L Pentelute 1 3 4 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge MA 02139 USA blp@mit.edu.
  • 2 Calico Life Sciences LLC 1170 Veterans Boulevard South San Francisco CA 94080 USA aaronnile@calicolabs.com.
  • 3 The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology 500 Main Street Cambridge MA 02142 USA.
  • 4 Center for Environmental Health Sciences, Massachusetts Institute of Technology 77 Massachusetts Avenue Cambridge MA 02139 USA.
  • 5 Broad Institute of MIT and Harvard 415 Main Street Cambridge MA 02142 USA.
PMID: 38020382 DOI: 10.1039/d3sc02782a
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.

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