Cyclic Peptide PROTACs Restore VHL-Mediated HIF-1α Degradation in Hypoxia

Abstract We report a systematic approach to convert cyclic peptide protein–protein interaction (PPI) inhibitors into functional degraders. We compare traditional PEG-based linkers with custom bifunctional amino acids that embed a Von Hippel-Lindau (VHL)-recruiting ligand and variable-length linkers for direct incorporation into cyclic peptides during solid-phase peptide synthesis (SPPS). Using an optimized split-intein circular ligation of peptides and proteins (SICLOPPS)-derived hypoxia-inducible factor 1 (HIF-1) inhibitor as the warhead, we generate cyclic peptide PROTACs (CP-PROTACs) that form a ternary complex with VHL and degrade HIF-1α across multiple cancer cell lines, suppressing hypoxia-response signaling. Degradation is oxygen-state dependent, being robust at 3% oxygen but lost at 1% oxygen. We show that the degrader remains engagement- and degradation-competent at 1% oxygen but is outpaced by HIF-1α resynthesis, revealing a kinetic ceiling on proteolytic-targeting chimeras (PROTAC) efficacy against rapidly replenished proteins. The modular amino acid building blocks reported provide a generalizable blueprint for converting cyclic peptides into degraders, extending targeted protein degradation to previously intractable proteins.