Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics

Abstract

With the development of modern chemistry and biology, non-proteinogenic amino acids (NPAAs) have become a powerful tool for developing peptide-based drug candidates. Drug-like properties of peptidic medicines, due to the smaller size and simpler structure compared to large proteins, can be changed fundamentally by introducing NPAAs in its sequence. While peptides composed of natural amino acids can be used as drug candidates, the majority have shown to be less stable in biological conditions. The impact of NPAA incorporation can be extremely beneficial in improving the stability, potency, permeability, and bioavailability of peptide-based therapies. Conversely, undesired effects such as toxicity or immunogenicity should also be considered. The impact of NPAAs in the development of peptide-based therapeutics is reviewed in this article. Further, numerous examples of peptides containing NPAAs are presented to highlight the ongoing development in peptide-based therapeutics.

Membrane-Interacting Antifungal Peptides

“…Nonetheless, they are also more prone to degradation as compared to small moleculebased drugs. To overcome this limitation, non-natural amino acids and/or cyclization can be introduced to enhance peptide stability (Ding et al, 2020). Numerous AMP-based drugs are currently evaluated in clinical trials [as reviewed in Mookherjee et al (2020)] for a variety of potential applications, such as antimicrobial therapies and immunomodulatory therapies.…”

Discovery of KV1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges

“…Due to the great diversity in their physicochemical characteristics, these NPAAs can be used to improve peptide stability, permeability. and potency, thereby contributing to better bioavailability 136 . First of all, stability can be improved by stabilizing the backbone configuration or eliminating the enzyme recognition sites, avoiding proteolysis.…”

Peptide Gelators to Template Inorganic Nanoparticle Formation

“…Firstly, peptides, especially short ones, can readily be prepared by well-established solid-phase methods, also for ease of purification [ 2 ]. Secondly, they allow greater chemical diversity, relative to other classes of compounds, which has been further expanded by the introduction of a large variety of non-natural amino acids [ 3 , 4 ]. Thirdly, as the complex function of proteins can be pinned to specific sets of peptide sequences, it has been shown that peptides can encode for at least some of protein functionalities [ 5 ].…”