Engineered coiled-coil HIF1α protein domain mimic

Dustin Britton, Olga Katsara, Orin Mishkit, Andrew Wang, Neelam Pandya, Chengliang Liu, Heather Mao, Jakub Legocki, Sihan Jia, Yingxin Xiao, Orlando Aristizabal, Deven Paul, Yan Deng, Robert Schneider, Youssef Z. Wadghiri, Jin Kim Montclare

Research output: Contribution to journalArticlepeer-review

Abstract

The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and in vivo tumor targeting capability.

Original languageEnglish (US)
JournalBiomaterials Science
DOIs
StateAccepted/In press - 2024

ASJC Scopus subject areas

  • Biomedical Engineering
  • General Materials Science

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