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Review
. 2020 Sep;52(9):1207-1226.
doi: 10.1007/s00726-020-02890-9. Epub 2020 Sep 18.

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

Yun Ding  1 , Joey Paolo Ting  1 , Jinsha Liu  1 , Shams Al-Azzam  2 , Priyanka Pandya  1 , Sepideh Afshar  3
Affiliations
Review

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

Yun Ding et al. Amino Acids. 2020 Sep.

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.

Keywords: Development; Discovery; Non-proteinogenic amino acid; Peptide therapeutic.

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Conflict of interest statement

The authors YD, JPT, JL, SAA, PP, and SA of this manuscript have no competing interest.

Figures

Fig. 1
Fig. 1
Different strategies of non-proteogenic amino acids incorporation to improve the pharmacokinetic properties of peptide drugs. The wide array of available NPAAs can be introduced in the peptide therapeutics to increase stability, potency, and permeability, which can lead to improved oral bioavailability
Fig. 2
Fig. 2
Peptide building blocks and modifications. Different building blocks such as NAA and NPAA with an l or d configuration can be incorporated into the peptide chain. Some of these building blocks can be further modified using a variety of post-translational modifications
Fig. 3
Fig. 3
Schematic of orally bioavailable peptide therapeutics for local and systemic delivery. Non-proteinogenic amino acids are introduced in the peptide sequence to overcome challenges of oral delivery
Fig. 4
Fig. 4
Incorporation and utilization of NPAAs in peptide display platforms. NPAAs can be incorporated in different peptide display platforms such as OBOC, ribosome display, and mRNA display. These random peptide libraries can be used for affinity selection to identify hit candidates already containing NPAAs. Hit candidates can be improved for stability, potency, permeability, and oral bioavailability
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