Rational design and synthesis of orally bioavailable peptides guided by NMR amide temperature coefficients

Wang, Conan K., Northfield, Susan E., Colless, Barbara, Chaousis, Stephanie, Hamernig, Ingrid, Lohman, Rink-Jan, Nielsen, Daniel S., Schroeder, Christina I., Liras, Spiros, Price, David, A., Fairlie, David and Craik, David J. (2014) Rational design and synthesis of orally bioavailable peptides guided by NMR amide temperature coefficients. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 111 49: 17504-17509. doi:10.1073/pnas.1417611111


Author Wang, Conan K.
Northfield, Susan E.
Colless, Barbara
Chaousis, Stephanie
Hamernig, Ingrid
Lohman, Rink-Jan
Nielsen, Daniel S.
Schroeder, Christina I.
Liras, Spiros
Price, David, A.
Fairlie, David
Craik, David J.
Title Rational design and synthesis of orally bioavailable peptides guided by NMR amide temperature coefficients
Journal name Proceedings of the National Academy of Sciences of the United States of America (PNAS)   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2014-11-21
Year available 2014
Sub-type Article (original research)
DOI 10.1073/pnas.1417611111
Open Access Status Not Open Access
Volume 111
Issue 49
Start page 17504
End page 17509
Total pages 6
Place of publication Washington, DC United States
Publisher National Academy of Sciences
Collection year 2015
Language eng
Formatted 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.
Keyword Cyclic Peptide
Permeability
N methylation
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 09 Dec 2014, 10:45:05 EST by Susan Allen on behalf of Institute for Molecular Bioscience