Title |
Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients
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Published in |
Proceedings of the National Academy of Sciences of the United States of America, November 2014
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DOI | 10.1073/pnas.1417611111 |
Pubmed ID | |
Authors |
Conan K. Wang, Susan E. Northfield, Barbara Colless, Stephanie Chaousis, Ingrid Hamernig, Rink-Jan Lohman, Daniel S. Nielsen, Christina I. Schroeder, Spiros Liras, David A. Price, David P. Fairlie, David J. Craik |
Abstract |
Enhancing the oral bioavailability of peptide drug leads is a major challenge in drug design. As such, methods to address this challenge are highly sought after by the pharmaceutical industry. Here, we propose a strategy to identify appropriate amides for N-methylation using temperature coefficients measured by NMR to identify exposed amides in cyclic peptides. N-methylation effectively caps these amides, modifying the overall solvation properties of the peptides and making them more membrane permeable. The approach for identifying sites for N-methylation is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Five leucine-rich peptide scaffolds are reported with selectively designed N-methylated derivatives. In vitro membrane permeability was assessed by parallel artificial membrane permeability assay and Caco-2 assay. The most promising N-methylated peptide was then tested in vivo. Here we report a novel peptide (15), which displayed an oral bioavailability of 33% in a rat model, thus validating the design approach. We show that this approach can also be used to explain the notable increase in oral bioavailability of a somatostatin analog. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Spain | 1 | <1% |
Unknown | 184 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 51 | 28% |
Student > Ph. D. Student | 44 | 24% |
Student > Bachelor | 12 | 6% |
Student > Master | 9 | 5% |
Professor | 7 | 4% |
Other | 22 | 12% |
Unknown | 40 | 22% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 84 | 45% |
Biochemistry, Genetics and Molecular Biology | 15 | 8% |
Agricultural and Biological Sciences | 15 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 8 | 4% |
Medicine and Dentistry | 7 | 4% |
Other | 14 | 8% |
Unknown | 42 | 23% |