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

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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.

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Most cited references 183

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Molecular properties that influence the oral bioavailability of drug candidates.

Daniel F Veber, Stephen R Johnson, Hung-Yuan Cheng … (2002)

Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area equal to or less than 140 A(2) (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examined. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a negative effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examined here for the in vivo clearance rate in the rat.

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Therapeutic peptides: Historical perspectives, current development trends, and future directions

Michael K. Dunn, Jolene L. Lau (2018)

Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clinical development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chemistry efforts. We maintain a comprehensive dataset on peptides that have entered human clinical studies that includes over 150 peptides in active development today. Here we provide an overview of the peptide therapeutic landscape, including historical perspectives, molecular characteristics, regulatory benchmarks, and a therapeutic area breakdown.

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The Discovery and Development of Liraglutide and Semaglutide

Lotte Knudsen, Jesper Lau (2019)

The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.

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Author and article information

Contributors

Sepideh Afshar:

ORCID: http://orcid.org/0000-0002-9105-3946

afshar_sepideh@lilly.com

Journal

Journal ID (nlm-ta): Amino Acids

Journal ID (iso-abbrev): Amino Acids

Title: Amino Acids

Publisher: Springer Vienna (Vienna )

ISSN (Print): 0939-4451

ISSN (Electronic): 1438-2199

Publication date (Electronic): 18 September 2020

Publication date PMC-release: 18 September 2020

Publication date (Print): 2020

Volume: 52

Issue: 9

Pages: 1207-1226

Affiliations

[1 ]GRID grid.417540.3, ISNI 0000 0000 2220 2544, Protein Engineering, Lilly Biotechnology Center, , Eli Lilly and Company, ; San Diego, CA 92121 USA

[2 ]Professional Scientific Services, Eurofins Lancaster Laboratories, Lancaster, PA 17605 USA

Author notes

Handling Editor: J. D. Wade.

Author information

Yun Ding http://orcid.org/0000-0001-6234-7198

Sepideh Afshar http://orcid.org/0000-0002-9105-3946

Article

Publisher ID: 2890

DOI: 10.1007/s00726-020-02890-9

PMC ID: 7544725

PubMed ID: 32945974

SO-VID: 16c10d39-94fd-43d6-bc78-2ec429638dff

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 24 June 2020

Date accepted : 5 September 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100004312, Eli Lilly and Company;

Funded by: Eurofin Scientific Inc

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: non-proteinogenic amino acid,peptide therapeutic,discovery,development

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ScienceOpen disciplines: Genetics

Keywords: non-proteinogenic amino acid, peptide therapeutic, discovery, development

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

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