Engineered coiled-coil HIF1α protein domain mimic

• Published in: Biomaterials science Vol. 12; no. 11; pp. 2951 - 2959
• Main Authors: Britton, Dustin, Katsara, Olga, Mishkit, Orin, Wang, Andrew, Pandya, Neelam, Liu, Chengliang, Mao, Heather, Legocki, Jakub, Jia, Sihan, Xiao, Yingxin, Aristizabal, Orlando, Paul, Deven, Deng, Yan, Schneider, Robert, Wadghiri, Youssef Z, Montclare, Jin Kim
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 28.05.2024
• Subjects: Animals; Cartilage Oligomeric Matrix Protein - chemistry; Cartilage Oligomeric Matrix Protein - metabolism; Cell Line, Tumor; Coils; E1A-Associated p300 Protein - chemistry; E1A-Associated p300 Protein - metabolism; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Mice; Protein Domains; Protein Engineering; Proteins; Self-assembly; Tumor Microenvironment; Tumors
• ISSN: 2047-4830; 2047-4849; 2047-4849
• DOI: 10.1039/d4bm00354c

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. Multivalent assembled proteins (MAPs) as protein domain mimics (PDMs) of HIF1α allows for improved tumor targeting.