Conditional Stabilization of the Hypoxia-Inducible Factor HIF1α- Photoswitchable Stapled Peptides Prevent Elongin...

Oxygen levels and its distribution are tightly regulated due to their critical impact on health. Hypoxia-inducible factors (HIFs) are traditionally recognized as key regulators of the transcriptional response to low oxygen (hypoxia). Recent research expanded their functions, highlighting their potential as therapeutic targets. Despite these advances, there is still a need for chemical biology tools that offer precise spatiotemporal control within the HIF network and output. Here, we introduce an optochemical approach that enables significant differences in expression of HIF1α-target genes depending on the photostationary state (PSS). Our photoswitchable stapled peptide PS_B-BCB-04 stabilized HIF1α under normoxic conditions by targeting EloBC (k_i  =  7.9 ± 1.3 nM) and preventing VHL-mediated degradation. Visible light allowed reversible regulation of peptide conformation, which entailed a sevenfold difference in its EloBC-binding capacity. In a proof-of-concept study, we demonstrated that inhibition of HIF1α degradation enabled isomer-specific expression of the vascular endothelial growth factor (VEGFA) in prostate cancer cells. Our results validated the potential of photopharmacological stabilization of HIF1α and provided a new toolbox for on-demand photocontrol over the HIF-signaling pathway as well as VHL-mediated degradation.