Large Scale Synthesis of Native Turn and Helix Mimics Stabilized by a Generic Hydrogen Bond Surrogate

Abstract Short Turn and Helix mimics frequently represent molecular recognition surfaces perturbing bio-relevant protein-biomolecular interfaces. Generic methods that can stabilize short peptides into turns or helices by retaining all recognition elements, have tremendous applications in drug discovery. Here, a versatile modular synthetic protocol is presented for stabilizing turns and helices of different sizes by replacing their ring-closing hydrogen bonds with a generic three-carbon covalent surrogate. Two Fukuyama-Mitsunobu reactions insert the surrogate between desired residues in high yields and purity. Coupling with turn size-dependent oligopeptides containing both sterically restricted and non-coded residues, followed by macrolactamization yield a variety of stabilized turns. Short peptide extensions at the C-terminus of these turns yield stabilized 310-helices and α-helices. This solution-phase synthetic approach provides combinatorial access to libraries of stabilized turns and helices with all their native residues retained, in >100 mmole scales, in about one week per stabilized mimic, to technicians with postgraduate level training.