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

Abstract

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.