The DOI matches its Crossref record; 196 of the 196 references it cites were found in a registry or an index.
Orally Absorbed Cyclic Peptides
Abstract
Peptides and proteins are not orally bioavailable in mammals, although a few peptides are intestinally absorbed in small amounts. Polypeptides are generally too large and polar to passively diffuse through lipid membranes, while most known active transport mechanisms facilitate cell uptake of only very small peptides. Systematic evaluations of peptides with molecular weights above 500 Da are needed to identify parameters that influence oral bioavailability. Here we describe 125 cyclic peptides containing four to thirty-seven amino acids that are orally absorbed by mammals. Cyclization minimizes degradation in the gut, blood, and tissues by removing cleavable N- and C-termini and by shielding components from metabolic enzymes. Cyclization also folds peptides into bioactive conformations that determine exposure of polar atoms to solvation by water and lipids and therefore can influence oral bioavailability. Key chemical properties thought to influence oral absorption and bioavailability are analyzed, including molecular weight, octanol-water partitioning, hydrogen bond donors/acceptors, rotatable bonds, and polar surface area. The cyclic peptides violated to different degrees all of the limits traditionally considered to be important for oral bioavailability of drug-like small molecules, although fewer hydrogen bond donors and reduced flexibility generally favored oral absorption.
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Macrocyclic Peptides as Drug Candidates: Recent Progress and Remaining Challenges
Vinogradov, A. A., Yin, Y., & Suga, H. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.8b13178 · Cited by 848
RNA Display Methods for the Discovery of Bioactive Macrocycles
Huang, Y., Wiedmann, M. M., & Suga, H. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00430 · Cited by 298
Tanada, M., Tamiya, M., Matsuo, A., Chiyoda, A., Takano, K., Ito, T., Irie, M., Kotake, T., Takeyama, R., Kawada, H., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c03886 · Cited by 188
Peptides as drug delivery vehicles across biological barriers
Ghosh, D., Peng, X., Leal, J., & Mohanty, R. P. (2018) · Journal of Pharmaceutical Investigation · doi:10.1007/s40005-017-0374-0 · Cited by 102
Drug‐Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side‐Chain Lipophilicity
Furukawa, A., Schwochert, J., Pye, C. R., Asano, D., Edmondson, Q. D., Turmon, A. C., Klein, V. G., Ono, S., Okada, O., & Lokey, R. S. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202004550 · Cited by 79
Metadata
- Authors
- Nielsen, D. S., Shepherd, N. E., Xu, W., Lucke, A. J., Stoermer, M. J., & Fairlie, D. P.
- Venue
- Chemical Reviews
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-05-25
- Volume
- 117
- Issue
- 12
- Pages
- 8094-8128
- ISSN
- 0009-2665 (ISSN-L)
- 1520-6890
- OpenAlex
- W2618351167
- Cited by
- 445
- References
- 196
- FWCI
- 2.95
- Type
- journal article
- Language
- en
- Open access
- closed
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- Nielsen, D. S., Shepherd, N. E., Xu, W., Lucke, A. J., Stoermer, M. J., & Fairlie, D. P. (2017). Orally Absorbed Cyclic Peptides. Chemical Reviews. https://doi.org/10.1021/acs.chemrev.6b00838
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