In vitro selection of highly N-alkylated cyclic peptides for targeting intracellular protein-protein interactions

Peptide Drug Discovery poor bio-activity membrane permeable metabolically stable Drug potent bio-activity membrane permeable metabolically stable Undrug-like hit potent bio-activity poor membrane permeability poor metabolic stability Small conformational change Drug-like hit moderate bio-activity (potentially) membrane permeable metabolically stable Conformational change Modification without scaffold hopping Conclusion Cyclic peptides were generated from our designated library contained 5-7 NAAs in 11-residue residues for KRAS. AP8784 from our library afforded orally available LUNA18 without scaffold hopping, which supports the validity of our concept.