Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges
Abstract
Peptides as a therapeutic modality attract much attention due to their synthetic accessibility, high degree of specific binding, and the ability to target protein surfaces traditionally considered "undruggable". Unfortunately, at the same time, other pharmacological properties of a generic peptide, such as metabolic stability and cell permeability, are quite poor, which limits the success of de novo discovered biologically active peptides as drug candidates. Here, we review how macrocyclization as well as the incorporation of nonproteogenic amino acids and various conjugation strategies may be utilized to improve on these characteristics to create better drug candidates. We analyze recent progress and remaining challenges in improving individual pharmacological properties of bioactive peptides, and offer our opinion on interfacing these, often conflicting, considerations, to create balanced drug candidates as a potential way to make further progress in this area.
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The ynamide-mediated esterification method could be extended to thioesterification, allowing preparation of various thioesters using -SH nucleophiles, especially peptide thioesters.
“Additionally, this method could also be extended to the thioesterification reaction, allowing us to prepare various thioesters using -SH nucleophiles, especially peptide thioesters (Scheme 9d).45”
From Ynamide Coupling Reagents: Origin and Advances (2024) · cites this paper as [45]
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Therapeutic Peptides: Current Applications and Future Directions
Wang, L., Wang, N., Zhang, W., Cheng, X., Yan, Z., Shao, G., Wang, X., Wang, R., & Fu, C. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00904-4 · Cited by 2,131 · see citing works
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- Authors
- Vinogradov, A. A., Yin, Y., & Suga, H.
- Affiliations
- The University of Tokyo (JP)
- Corresponding author
- Suga, Hiroaki
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-02-15
- Volume
- 141
- Issue
- 10
- Pages
- 4167-4181
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2912930263
- Cited by
- 848
- References
- 4
- Citations by year
- 2026: 127 · 2025: 147 · 2024: 142 · 2023: 106 · 2022: 124 · 2021: 99 · 2020: 79 · 2019: 24
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Agency for Medical Research and Development (am0101090j0001, am0301001h0004)
- Core Research for Evolutional Science and Technology (JPMJCR12L2)
- Japan Society for the Promotion of Science (26220204)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Physical Sciences › Chemistry › Organic Chemistry › Supramolecular Chemistry and Complexes
- Keywords
- macrocyclic peptides, macrocyclization, peptide conjugation, metabolic stability, membrane permeability
- MeSH terms
- Animals, Cell Membrane Permeability, Cyclization, Humans, Peptides, Cyclic, Protein Stability, Drug Discovery
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