The study describes the development and characterization of a novel chemical strategy called hydrocarbon stapling, which enhances the pharmacological properties of BH3 peptides. This method involves using α,α-disubstituted non-natural amino acids to create a hydrocarbon "staple" that stabilizes the α-helical structure of the BH3 domain. The resulting peptides, called Stabilized Alpha-Helix of BCL-2 Domains (SAHBs), exhibit increased helicity, protease resistance, and cell permeability. SAHBs specifically bind to the binding pockets of multidomain BCL-2 members, enhancing their affinity and biological activity. A SAHB of the BH3 domain from the BID protein was shown to activate the apoptotic pathway in leukemia cells, leading to cytochrome c release and apoptosis. Additionally, SAHB effectively inhibited the growth of human leukemia xenografts in vivo, demonstrating its potential as a therapeutic agent. The study highlights the utility of hydrocarbon stapling in modulating protein-protein interactions and suggests its potential for therapeutic applications in cancer and other diseases.The study describes the development and characterization of a novel chemical strategy called hydrocarbon stapling, which enhances the pharmacological properties of BH3 peptides. This method involves using α,α-disubstituted non-natural amino acids to create a hydrocarbon "staple" that stabilizes the α-helical structure of the BH3 domain. The resulting peptides, called Stabilized Alpha-Helix of BCL-2 Domains (SAHBs), exhibit increased helicity, protease resistance, and cell permeability. SAHBs specifically bind to the binding pockets of multidomain BCL-2 members, enhancing their affinity and biological activity. A SAHB of the BH3 domain from the BID protein was shown to activate the apoptotic pathway in leukemia cells, leading to cytochrome c release and apoptosis. Additionally, SAHB effectively inhibited the growth of human leukemia xenografts in vivo, demonstrating its potential as a therapeutic agent. The study highlights the utility of hydrocarbon stapling in modulating protein-protein interactions and suggests its potential for therapeutic applications in cancer and other diseases.