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

Pritha Ghosh, Nishant Raj, Hitesh Verma, Monika Patel, Sohini Chakraborti, Bhavesh Khatri, Chandrashekar M. Doreswamy, S. R. Anandakumar, Srinivas Seekallu, M. B. Dinesh, Gajanan Jadhav, Prem Narayan Yadav and Jayanta Chatterjee ()
Additional contact information
Pritha Ghosh: Indian Institute of Science
Nishant Raj: Indian Institute of Science
Hitesh Verma: Indian Institute of Science
Monika Patel: Neuroscience & Ageing Biology, CSIR-CDRI
Sohini Chakraborti: Indian Institute of Science
Bhavesh Khatri: Indian Institute of Science
Chandrashekar M. Doreswamy: Anthem Biosciences Pvt. Ltd.
S. R. Anandakumar: Anthem Biosciences Pvt. Ltd.
Srinivas Seekallu: Anthem Biosciences Pvt. Ltd.
M. B. Dinesh: Indian Institute of Science
Gajanan Jadhav: Eurofins Advinus Biopharma Services India Pvt. Ltd.
Prem Narayan Yadav: Neuroscience & Ageing Biology, CSIR-CDRI
Jayanta Chatterjee: Indian Institute of Science

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-41748-y Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41748-y

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-41748-y

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().