Inhibition of Hypoxia-Inducible Transcription Factor (HIF-1a) Signaling with Sulfonyl-?-AApeptide Helices

The development of inhibitors that selectively block protein-protein interactions (PPIs) is crucial for chemical biology, medicinal chemistry, and biomedical sciences. Herein, we reported the design, synthesis, and investigation of sulfonyl-?-AApeptide as an alternative strategy of canonical peptide-based inhibitors to disrupt hypoxia-inducible factor 1a (HIF-1a) and p300 PPI by mimicking the helical domain of HIF-1a involved in the binding to p300. The designed molecules recognized the p300 protein with high affinity and potently inhibited the hypoxia-inducible signaling pathway. Gene expression profiling supported the idea that the lead molecules selectively inhibited hypoxia-inducible genes involved in the signaling cascade. Our studies also demonstrated that both helical faces consisting of either chiral side chains or achiral sulfonyl side chains of sulfonyl-?-AApeptides could be adopted for mimicry of the a-helix engaging in PPIs. Furthermore, these sulfonyl-?-AApeptides were cell-permeable and exhibited favorable stability and pharmacokinetic profiles. Our results could inspire the design of helical sulfonyl-?-AApeptides as a general strategy to mimic the protein helical domain and modulate many other PPIs.