Traditionally, the set of permeable macrocyclic peptides was expanded from privileged, natural product scaffolds by discrete synthesis and careful side chain variation. Macrocyclic peptides that achieve passive cellular permeability sample conformations with low desolvation penalty upon transfer from aqueous to membrane environments. More recently, the basic principles governing passive permeability were applied to the prospective design of macrocyclic peptides with passive membrane permeability and oral bioavailability. However, there remains the broad challenge of chemical diversity sufficient to enable regular identification of novel protein ligands. By contrast, cell-free, template-directed ribosomal peptide synthesis offers enormous, highly diverse libraries of macrocyclic peptides containing both standard and non-standard amino acids and entry to macrocyclic peptide ligands with exquisite affinity and selectivity. However, in this context, ligands are identified in the absence of selection pressure for cellular permeability. Herein, we present 6-, 7-, and 8-mer macrocyclic peptides with library-compatible standard and non-standard amino acids, library-enabled backbones, computationally vetted N-methylation patterns, and experimentally validated oral bioavailability.

Design of technology-compatible cyclic peptide scaffolds with oral bioavailability

253rd National Meeting (2017)

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