Helix-constrained polypeptides have attracted great interest for modulating protein-protein interactions (PPI). It is not known which are the most effective helix-inducing strategies for designing PPI agonists/antagonists. Cyclization linkers (X-1-X-5) were compared here, using circular dichroism and 2D NMR spectroscopy, for a-helix induction in simple model pentapeptides, Ac-cyclo(1,5)-[X-1-Ala-Ala-Ala-X-5]-NH2, in water. In this very stringent test of helix induction, a Lys1 -> Asp5 lactam linker conferred greatest alpha-helicity, hydrocarbon and triazole linkers induced a mix of alpha- and 3(10)-helicity, while thio-and dithioether linkers produced less helicity. The lactam-linked cyclic pentapeptide was also the most effective a-helix nucleator attached to a 13-residue model peptide
