Veteran peptide chemist Horst Kessler (TU Munich) has a good review on the effects of N-methylation of peptides and proteins in a recent issue of Angewandte Chemie. N-methylation has been an interesting and frequently productive strategy for a long time, but the main problem was that the chemistry needed to implement it wasn't there yet. But thanks to new developments chemists have caught up and selective N-methylation of amides no longer needs to be the rate-limiting step that it was.
N-methylation has a variety of interesting and potentially very useful effects on small molecule and peptide conformation and function. For one thing, N-methylated amide bonds have a different distribution of cis and trans forms which is somewhat more evenly distributed than that in non N-methylated amide bonds which dominantly prefer the trans conformation. This can significantly tweak the distribution of conformations in solution.
From a biological standpoint things get even more interesting. N-methylation makes the molecule more lipophilic and therefore more membrane-permeable, improving cell penetration. It gets rid of one hydrogen bonding N-H bond. This can sometimes have an unfavorable effect on permeability if that N-H forms an intramolecular hydrogen bond, but often it can help. Intramolecular hydrogen bonds are another valuable tactic for hiding polar surface area and improving permeability. The ideal situation is a combination of both N-methylation and intramolecular hydrogen bonding, exemplified by the archetypal "large", complex, biologically active drug, cyclosporine. Recentstudies by the Jacobson (UCSF) and Lokey (groups) have described strategies for both specific N-methylation chemistry and for predicting permeability using computational calculations.
Finally, N-methylation can prevent recognition and cleavage by peptidases which recognize "normal" amide bonds, especially when the N-methylated amides are part of a cyclic peptide. All these factors can significantly improve bioavailability. Kessler talks about all of them and illustrates these principles with a few striking examples, including somatostatin, amanitin and melanocortin. Many of these sport similar motifs, leading to ideas for possible design of standardized building blocks for improving permeability and bioavailability. The piece is worth a look if you are into developing peptides and peptidomimetics as drugs or even more generally if you are interested in peptide and small molecule conformations.
N-methylation has a variety of interesting and potentially very useful effects on small molecule and peptide conformation and function. For one thing, N-methylated amide bonds have a different distribution of cis and trans forms which is somewhat more evenly distributed than that in non N-methylated amide bonds which dominantly prefer the trans conformation. This can significantly tweak the distribution of conformations in solution.
From a biological standpoint things get even more interesting. N-methylation makes the molecule more lipophilic and therefore more membrane-permeable, improving cell penetration. It gets rid of one hydrogen bonding N-H bond. This can sometimes have an unfavorable effect on permeability if that N-H forms an intramolecular hydrogen bond, but often it can help. Intramolecular hydrogen bonds are another valuable tactic for hiding polar surface area and improving permeability. The ideal situation is a combination of both N-methylation and intramolecular hydrogen bonding, exemplified by the archetypal "large", complex, biologically active drug, cyclosporine. Recentstudies by the Jacobson (UCSF) and Lokey (groups) have described strategies for both specific N-methylation chemistry and for predicting permeability using computational calculations.
Finally, N-methylation can prevent recognition and cleavage by peptidases which recognize "normal" amide bonds, especially when the N-methylated amides are part of a cyclic peptide. All these factors can significantly improve bioavailability. Kessler talks about all of them and illustrates these principles with a few striking examples, including somatostatin, amanitin and melanocortin. Many of these sport similar motifs, leading to ideas for possible design of standardized building blocks for improving permeability and bioavailability. The piece is worth a look if you are into developing peptides and peptidomimetics as drugs or even more generally if you are interested in peptide and small molecule conformations.