Backbone N-methylation is common among peptide natural products and has a substantial impact on both the physical properties and the conformational states of cyclic peptides. However, the specific impact of N-methylation on passive membrane diffusion in cyclic peptides has not been investigated systematically. Here we report a method for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability. The selectivity and degree of N-methylation of the cyclic peptide was dependent on backbone stereochemistry, suggesting that conformation dictates the regiochemistry of the N-methylation reaction. The permeabilities of the N-methyl variants were corroborated by computational studies on a 1,024-member virtual library of N-methyl cyclic peptides. One of the most permeable compounds, a cyclic hexapeptide (molecular mass = 755 Da) with three N-methyl groups, showed an oral bioavailability of 28% in rat.
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The synthesis and analytical results were supported by US National Institutes of Health grant GM084530-06 (R.S.L.). The computational results were supported by US National Institutes of Health grant R01-GM086602 to M.P.J. M.P.J. is a consultant to Schrodinger LLC. Cell-based assays and in vivo pharmacokinetics were provided by Pfizer.
The authors declare no competing financial interests.
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White, T., Renzelman, C., Rand, A. et al. On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat Chem Biol 7, 810–817 (2011) doi:10.1038/nchembio.664
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