Design of Thioether Cyclic Peptide Scaffolds with Passive Permeability and Oral Exposure

Advances in the design of permeable
peptides and in the synthesis
of large arrays of macrocyclic peptides with diverse amino acids have
evolved on parallel but independent tracks. Less precedent combines
their respective attributes, thereby limiting the potential to identify
permeable peptide ligands for key targets. Herein, we present novel
6-, 7-, and 8-mer cyclic peptides (MW 774–1076 g·mol–1) with passive permeability and oral exposure that
feature the amino acids and thioether ring-closing common to large
array formats, including DNA- and RNA-templated synthesis. Each oral
peptide herein, selected from virtual libraries of partially N-methylated
peptides using in silico methods, reflects the subset
consistent with low energy conformations, low desolvation penalties,
and passive permeability. We envision that, by retaining the backbone
N-methylation pattern and consequent bias toward permeability, one
can generate large peptide arrays with sufficient side chain diversity
to identify permeability-biased ligands to a variety of protein targets.