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Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.


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.

SUBMITTER: Wang CK 

PROVIDER: S-EPMC4267368 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.

Wang Conan K CK   Northfield Susan E SE   Colless Barbara B   Chaousis Stephanie S   Hamernig Ingrid I   Lohman Rink-Jan RJ   Nielsen Daniel S DS   Schroeder Christina I CI   Liras Spiros S   Price David A DA   Fairlie David P DP   Craik David J DJ  

Proceedings of the National Academy of Sciences of the United States of America 20141201 49


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 pe  ...[more]

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