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α-Helices constitute the largest class of protein secondary structures and play a major role in mediating protein−protein interactions. Development of stable mimics of short α-helices would be invaluable for inhibition of protein−protein interactions. This Account describes our efforts in developing a general approach for constraining short peptides in α-helical conformations by a main-chain hydrogen bond surrogate (HBS) strategy. The HBS α-helices feature a carbon−carbon bond derived from a ring-closing metathesis reaction in place of an N-terminal intramolecular hydrogen bond between the peptide i and i + 4 residues. Our approach is centered on the helix−coil transition theory in peptides, which suggests that the energetically demanding organization of three consecutive amino acids into the helical orientation inherently limits the stability of short α-helices. The HBS method affords preorganized α-turns to …