Proteins are characterized by extensive hydrogen bonding that defines regular and irregular substructures. However, hydrogen bonds are weak and insufficient for stabilizing peptide conformation in water. Consequently, the biological activity of peptides is reduced. This led us to test whether a covalent mimic of the hydrogen bond could be used to stabilize peptide conformation in water. A solid-phase synthesis is described for replacing a main-chain hydrogen bond (NH --> O=CRNH) with a hydrazone link (N-N= CH-CH2CH2). in peptides. The synthesis is easy to implement, rapid, and capable of high yields. The replacement of a putative (i + 4 --> i) hydrogen bond with the hydrazone at the N terminus of acetyl-GLAGAEAAKA-NH2 (1) to give [JLAZ]AEAAKA-NH2 (2)converts it to a full-length ct-helix in water at ambient temperature as indicated by NMR spectroscopy. The observation of weak d(alpha N)(i, i + 3), medium d(NN)(i, i + 1), and strong d(alpha beta)(i, i + 3) NOEs that span 2 establish the formation of a full-length cc-helix in water; J(alpha N) coupling constants and amide proton chemical shifts and temperature coefficients are consistent with a model involving rapidly equilibrating extended and alpha-helical conformers. Substituting L-alanine with L-proline to give [JLPZ]AEAAKA-NH2 (3) enhances alpha-helix nucleation and shifts the equilibrium further toward full-length alpha-helix. The hydrazone link displays many of the properties required of a hydrogen bond mimic and could find use as a general means for constraining peptides to a range of biologically relevant conformations.