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

Ghosh, P and Raj, N and Verma, H and Patel, M and Chakraborti, S and Khatri, B and Doreswamy, CM and Anandakumar, SR and Seekallu, S and Dinesh, MB and Jadhav, G and Yadav, PN and Chatterjee, J (2023) An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides. In: Nature Communications, 14 (1).

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Official URL: https://doi.org/10.1038/s41467-023-41748-y


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. © 2023, Springer Nature Limited.

Item Type: Journal Article
Publication: Nature Communications
Publisher: Nature Research
Additional Information: The copyright for this article belongs to the Authors.
Keywords: amide; macrocyclic compound; somatostatin derivative; thioamide; amino acid; peptide; solvent, amino acid; bioavailability; chemical bonding; hydrogen; hydrophobicity; membrane; peptide; permeability; solvent, animal experiment; Article; controlled study; hydrogen bond; hypothesis; in vitro study; in vivo study; lipophilicity; male; membrane permeability; metabolic stability; molecular dynamics; nonhuman; permeability; rat; reduction (chemistry); substitution reaction; systemic circulation; animal; bioavailability; chemistry, Amides; Amino Acids; Animals; Biological Availability; Peptides; Permeability; Rats; Solvents; Thioamides
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Biological Sciences > Central Animal Facility (Formerly Primate Research Laboratory)
Date Deposited: 12 Dec 2023 04:34
Last Modified: 12 Dec 2023 04:34
URI: https://eprints.iisc.ac.in/id/eprint/83360

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