N-Methylation--An Important Approach towards Peptidomimetics
N- Methylation is an important approach for peptide backbone modifications.
N-Methylation is an important approach for peptide backbone modifications. Many natural peptides, isolated from plants, marine organisms, and various microorganisms contain N-methylation structure. These peptides exhibit important biological activities such as antitumor, antibiotic or immunosuppressive activities. Therefore, incorporation of N-methyl group into a peptide has been a powerful tool for the study of structure-activity relationship, and could lead to analogues with improved pharmacological properties.
Why do N-methylated peptides exhibit such great changes in biological activities? It is generally believed that these changes in biological activity are mainly due to the peptide structural changes from N- methylations:
Shifting the pure trans-configuration of many peptide bonds into a mixture of cis- and trans-configuration;
Increasing the steric hindrance of the peptide backbone;
Reducing intra- or inter-molecular hydrogen bonds;
Increasing the basicity of the attached carbonyl group and reducing its polarity.
These structural changes will lead to great changes in the pharmacological activity of the modified peptide.
TheN-methylation-scanning techniquewas originally proposed by Sugano, who synthesized a series of mono-N-methylated analogues of Endostatin (KFIGLM). These analogues from N-methylation on Ile or Met displayed much poorer biological activities, while the analogues from N-methylation on Phe or Leu exhibited the same activities as Endostatin. Based on these observations, Sugano designed and synthesized Eledoisin analog H-Lys- (Me)Phe-Ile-Gly- (Me) Leu-Met-NH2, which not only retained the biological activities, but also exhibited much better enzymatic stability.
In general, N-methylation of a peptide may lead to the followings:
Enhancing metabolic stability without effect on biological activities;
Reducing biological activities when the N- methylation amide bond is the active site;
Transforming an agonist into an antagonist.
In conclusion, the N-methylation-scanning technique in peptide backbone has provided an important approach for lead compound discovery and optimization in peptide drug research.