The 1,5-Disubstituted Tetrazole Ring as a cis-Amide Bond Surrogate

Proline occupies a special role among those amino acids incorporated into peptides and proteins by the normal ribosomal pathways, since it is the only residue that leads to an N -alkyl amide bond. In peptide natural products that often have special biosynthetic pathways or unusual posttranslational modifications, N -methyl amino acids are common and may play a special role because of their conformational properties, including their proclivity for cis-trans isomerism of the amide bond. Numerous peptides with important biological activities, such as cyclosporin and didemnin, contain N -methyl amino acids. Cis-trans isomerism of the N -alkyl amide bond involving the amino group can readily be observed (1 ) in the NMR of proline and N -methyl amino acid-containing peptides. In the case of angiotensin and thyroliberin (TRH) analogs, the quantity of cis -isomer in aqueous solution was correlated (2 ) with the biological activity. This suggested that the cis -isomer might be the one bound to the receptor and responsible for the observed biological activity. Bairaktari et al. (3 ) have reported that the normal amide bond between an He and Lys residues in the linear peptide, bombolitin, has the cis -conformation when bound to phospholipid micelles. In protei0n crystal structures, cis -amide bond conformations are occasionally observed for the normal, nonalkylated amide bond. A cis -amide bond predisposes the peptide for a reverse turn, a so-called Type VI β-turn. Brandl and Deber (4 ) have proposed that cis-trans isomerism of proline residue might play a role in transduction of transmembrane proteins.