Ubiquitin Pathway Blockade by Stapled Peptide Targeting of the Ubiquitin E1 Activating Enzyme
Access StatusFull text of the requested work is not available in DASH at this time ("dark deposit"). For more information on dark deposits, see our FAQ.
Morgan, Ann Maurine
MetadataShow full item record
CitationMorgan, Ann Maurine. 2019. Ubiquitin Pathway Blockade by Stapled Peptide Targeting of the Ubiquitin E1 Activating Enzyme. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractCellular homeostasis relies on a carefully-regulated balance between protein anabolism and catabolism. In eukaryotic organisms, the 8.6-kDa protein ubiquitin is the molecular tag that marks proteins whose cellular lifespans have expired and targets these proteins for proteasomal degradation. Nearly all ubiquitin is activated by the ubiquitin E1 activating enzyme UBE1, which in turn transfers ubiquitin to E2 conjugating and E3 ligase enzymes for specific attachment onto substrate proteins. Cancer cells are more vulnerable to inhibition of the ubiquitin pathway than other cell types, due to fundamentally high levels of proteotoxic stress caused by DNA damage and sustained growth signaling. An adenosine sulfamate UBE1 inhibitor has demonstrated broad preclinical and clinical efficacy for cancer treatment; however, treatment with the inhibitor induces rapid development of resistance through UBE1 active site mutations. Given the proven therapeutic relevance of UBE1 targeting, alternative pharmacologic modes of UBE1 inhibition are critically needed. Here, we apply all-hydrocarbon peptide stapling technology to develop a new class of UBE1 inhibitor compounds. We iteratively synthesized, characterized, and optimized stapled peptides modeled after a conserved α-helix of the E2 conjugating enzyme that dose-dependently bound and inhibited UBE1, ultimately inducing global blockade of the ubiquitin pathway. Our peptide inhibitor represents the first inhibitor of UBE1 that binds outside the active site, and has the potential to be further developed into a drug-like compound to advance a new therapeutic strategy of inducing proteotoxic stress for cancer treatment.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42106944
- FAS Theses and Dissertations