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.

N-MethylationThe N-methylation-scanning technique was 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;

Improving selectivity;

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.

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