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

• Published in: Nature communications Vol. 14; no. 1; p. 6050
• Main Authors: Ghosh, Pritha, Raj, Nishant, Verma, Hitesh, Patel, Monika, Chakraborti, Sohini, Khatri, Bhavesh, Doreswamy, Chandrashekar M., Anandakumar, S. R., Seekallu, Srinivas, Dinesh, M. B., Jadhav, Gajanan, Yadav, Prem Narayan, Chatterjee, Jayanta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 28.09.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Amino acids; Bioavailability; Chemical bonds; Chemical modification; Hydrogen; Hydrogen bonds; Hydrophobicity; Masking; Membrane permeability; Membranes; Oral administration; Peptides; Permeability; Pharmacology; Shielding; Solvents; Substitutes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41748-y

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 through the oral route in rats. Thioamidation of a bioactive macrocyclic peptide composed of polar amino acids results in analogs with longer duration of action in rats when delivered subcutaneously. These results highlight the potential of O to S substitution as a stable backbone modification in improving the pharmacological properties of peptide macrocycles.