Intramolecular hydrogen bondings and conformations of peptidic HIV-1 protease inhibitors studied by FTIR and CD spectroscopies

FTIR spectra of tripeptides IV-VIII and KNI-272, tetrapeptides IX-XIV, and their related compounds I-III were measured in dilute CH2Cl2 solution, in order to experimentally elucidate the active conformation of human immunodeficiency virus-1 protease inhibitor. CD spectra of VI and IX-XIV in 1,4-dioxane and IX and XI in H2O were also measured. For IV-XIV and KNI-272, an intramolecular hydrogen bond involving a five-membered ring was found between the OH and CO bonds. The intramolecular hydrogen bonds involving 10- and 5-membered rings were also found between the NH and CO bonds in IX-XIV and between the NH bond and the N atom in these compounds except for XI, respectively. These findings indicate that the degree of freedom in the motions of the peptide backbones and side chains in IX, X, and XII-XIV are highly restricted owing to these three hydrogen bonds. The CD data showed that these hydrogen bonds form in H2O. Anti-HIV-1 and HIV-1 PR inhibitory activities of V-XIV and KNI-272 were studied. On the basis of these results, we examined the structure-activity relationships for these compounds and estimated the active conformation of the tripeptides which do not form the 10-membered ring (β-turn conformation), compared with the conformation of the tetrapeptides.