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

doi:10.1039/D4BM00354C

Engineered coiled-coil HIF1α protein domain mimic†

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

*^acijk

Author affiliations

* Corresponding authors

^a Department of Chemical and Biomolecular Engineering, New York University Tandon School of Engineering, Brooklyn, New York, USA
E-mail: montclare@nyu.edu

^b Department of Microbiology, New York University School of Medicine, New York, New York, USA

^c Center for Advanced Imaging Innovation and Research (CAI2R), New York University School of Medicine, New York, New York, USA

^d Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, New York, USA

^e Department of Biomedical Engineering, State University of New York Downstate Medical Center, Brooklyn, New York, USA

^f College of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York, USA

^g Microscopy Laboratory, New York University Langone Health, New York, NY, USA

^h Department of Radiation Oncology, New York University School of Medicine, New York, New York, USA

ⁱ Department of Chemistry, New York University, New York, New York, USA

^j Department of Biomaterials, New York University College of Dentistry, New York, New York, USA

^k Department of Biomedical Engineering, New York University, New York, NY, USA

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.

Biomaterials Science

Engineered coiled-coil HIF1α protein domain mimic†

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Engineered coiled-coil HIF1α protein domain mimic

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