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

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

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

Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17504-9

Authors: Wang CK, Northfield SE, Colless B, Chaousis S, Hamernig I, Lohman RJ, Nielsen DS, Schroeder CI, Liras S, Price DA, Fairlie DP, Craik DJ

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.


PMID: 25416591 [PubMed - indexed for MEDLINE]



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