posted on 2023-09-06, 16:45authored byWei Jiang, Sami Abdulkadir, Xue Zhao, Peng Sang, Anastasia Tomatsidou, Xiujun Zhang, Yu Chen, Laurent Calcul, Xingmin Sun, Feng Cheng, Yong Hu, Jianfeng Cai
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-γ-AApeptide as an alternative
strategy of canonical peptide-based inhibitors to disrupt hypoxia-inducible
factor 1α (HIF-1α) and p300 PPI by mimicking the helical
domain of HIF-1α 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-γ-AApeptides
could be adopted for mimicry of the α-helix engaging in PPIs.
Furthermore, these sulfonyl-γ-AApeptides were cell-permeable
and exhibited favorable stability and pharmacokinetic profiles. Our
results could inspire the design of helical sulfonyl-γ-AApeptides
as a general strategy to mimic the protein helical domain and modulate
many other PPIs.