Potent Inhibition of HIF1α and p300 Interaction by a Constrained Peptide Derived from CITED2
Xuan Qin, Hailing Chen, Licheng Tu, Yue Ma, Na Liu, Haowei Zhang, Di Li, Bernd Riedl, Donald Bierer, Feng Yin, Zigang Li
Abstract
Disrupting the interaction between HIF1α and p300 is a promising strategy to modulate the hypoxia response of tumor cells. Herein, we designed a constrained peptide inhibitor derived from the CITED2/p300 complex to disturb the HIF1α/p300 interaction. Through truncation/mutation screening and a terminal aspartic acid-stabilized strategy, a constrained peptide was constructed with outstanding biochemical/biophysical properties, especially in binding affinity, cell penetration, and serum stability. To date, our study was the first one to showcase that stabilized peptides derived from CITED2 using helix-stabilizing methods acted as a promising candidate for modulating hypoxia-inducible signaling.