N‐methylation in amino acids and peptides: Scope and limitations

Abstract

Active pharmaceutical ingredients (APIs) can be divided into two types, namely chemical and biological entities. Traditionally, the former has been associated with the so-called small molecules. The revival of peptides in pharmaceutical industry results from their importance in many biological roles. However, low metabolic stability and the lack of oral availability of most peptides is the main drawback for peptide to fulfill that paradigmatic situation. In this regard, efforts are being channeled into addressing this issue by introducing restrictions into the flexible peptide backbone, mainly through N-methyl amino acids (NMAAs) or development of small cyclic peptides. In many cases, both the above restrictions are combined with the aim to enhance oral availability. The synthesis of NMAAs is complex and their introduction into the peptide chain brings additional synthetic challenges and also sometimes leads to side-reactions. Here we discuss the most efficient methods for the synthesis of NMAAs (either in solution or in solid phase) and also their introduction into peptide sequences. Special attention is also given to the detection of side reactions and the most efficient way to prevent them.

The impact of backbone N‐methylation on the structure‐activity relationship of Leu10‐teixobactin

“…For example, adding an additional methyl group to the already N ‐methylated N ‐terminus reduced potency by eight‐fold in the Arg 10 ‐teixobactin analogue . Given that N ‐methylation of one or more of the macrocyclic amides would likely introduce conformational or steric constraints and directly interfere with pyrophosphate binding, we focussed our current investigation to the effect of N ‐methylating residues 2‐7 of Leu 10 ‐teixobactin (Figure ). N ‐methylated d ‐Gln and d ‐ allo‐ Ile building blocks are not commercially available, in which case the alkylation was performed in situ .…”

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

“…There is an increased need for N ‐modified amino acids in designing peptides for therapeutic applications. However, the challenge is that their chemical synthesis is rather complex …”

The human gut chemical landscape predicts microbe-mediated biotransformation of foods and drugs

“…N-demethylases from Pseudomonas putida CBB5 ( ndmABCD ) (Summers et al, 2012) and Sphingobium sp. strain YBL2 ( pdmAB ) (Gu et al, 2013), both containing a Rieske non-heme iron oxygenase component, catalyze the N-demethylation of phenylurea herbicides and purine alkaloids, respectively; and range in size from 318 to 364 amino acids (Summers et al, 2012; Gu et al, 2013; Sharma et al, 2018). We clustered bacterial N-demethylase sequences described by Summers et al, and Tao et al, as well as protein sequences of >= 200 amino acids in length pulled based on text annotation from the RefSeq database (Pruitt et al, 2005) at 95% identity using the UCLUST algorithm (Edgar, 2010).…”