Replacement Of Peptide Bond Research Articles

Solid phase reductive alkylation techniques in analogue peptide bond and sidechain modification

The presence of a reduced peptide bond in a biologically active peptide usually has profound effects on conformation and potency. The CH 2NH group may be a useful tool for delineating important hydrogen-bonding points and may also offer a general strategy for the production of enzyme resistance and potent competitive antagonists containing minimal structural alteration. The introduction of the group by solid phase reductive alkylation with a protected amino acid aldehyde offers a rapid route to peptides containing one or even many bond replacements. Potential racemization problems have been investigated and appear to be mostly related to the LiAlH 4 reduction of ammo acid dimethylhydroxamates to the aldehydes. Conditions are presented which prevent this, however, prolonged storage of amino acid aldehydes does appear to result in substantial racemization. The stability of commonly used side chain protecting groups to synthetic conditions was also investigated. The reactivity of the CH 2NH group to subsequent coupling reactions is surprisingly low. Its utility as an additional derivatization point in analogue design is examined. Some biological effects of peptide bond replacement and also solid-phase N-alkylation of several types of peptide hormones are discussed.

In vitro activity profiles of cyclic and linear enkephalin pseudopeptide analogs

The peptide bond in the 4–5 position of the cyclic and linear enkephalin analogs H-Tyr-cyclo[-D-Lys-Gly-Phe-L(or D)-Leu-] and H-Tyr-D-Ala-Gly-Phe-L(or D)-Leu-OH was replaced by a thiomethylene ether linkage. Each of the configurational isomers of the cyclic pseudopeptide H-Tyr-cyclo[-D-Lys-Gly-Pheψ[CH 2S]L(or D)-Leu-] showed high potency in both the guinea pig ileum and the mouse vas deferens assay and, therefore, had no preference for either μ- or δ-opioid receptors, in contrast to the cyclic parent peptides H-Tyr-cyclo[-D-Lys-Gly-Phe-L(or D)-Leu-] which are μ-receptor selective. The loss of selectivity observed with the cyclic pseudopeptides may be due to the greater flexibility of their 18-membered ring structures as a consequence of the peptide bond substitution. The linear pseudopeptide analogs were both less potent and less δ-receptor selective than their parent compounds. These results indicate that thiomethylene ether peptide bond replacements can have a pronounced effect on the activity profile of peptide hormones and neurotransmitters.