Replacing standard amino acid residues with N-methyl amino acids can improve the pharmacokinetic properties of bioactive peptides and produce viable drug candidates. Many peptides are readily metabolized by proteolytic enzymes resulting in a short half-life in vivo. Introducing N-methyl amino acids generally increases the enzymatic stability of peptides, thus increasing their in vivo half-life. Most peptides either are hydrolyzed by digestive enzymes or are poorly absorbed through the intestine, resulting in poor oral availability. Substituting in N-methyl amino acids can increase peptidase stability and enhance intestinal permeability. Recent reports show that peptides rich in N-methyl phenylalanine passively diffuse across the blood-brain barrier and can be used as blood-brain barrier shuttles.
Including N-methyl amino acids in peptides can enhance activity and selectivity or convert an agonist to an antagonist. These changes are usually attributed to reduced backbone flexibility resulting from N-methyl groups. The N-methyl groups also inhibit hydrogen bonding, resulting in improved water solubility in hydrophobic Aβ peptides.
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