An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides.

ABSTRACT: Solvent shielding of the amide hydrogen bond donor (NH groups) through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. We demonstrate that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor (>C = O) through a thioamide substitution (>C = S). The membrane permeability is a consequence of the lower desolvation penalty of the macrocycle resulting from a concerted effect of conformational restriction, local desolvation of the thioamide bond, and solvent shielding of the amide NH groups. The enhanced permeability and metabolic stability on thioamidation improve the bioavailability of a macrocyclic peptide composed of hydrophobic amino acids when administered throu

SUBMITTER: Ghosh P 

PROVIDER: S-EPMC10539501 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature