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

Author

Listed:
  • 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
    Academy of Scientific and Innovative Research (AcSIR))

  • 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
    Academy of Scientific and Innovative Research (AcSIR))

  • Jayanta Chatterjee

    (Indian Institute of Science)

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.

Suggested Citation

  • 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 & Pr, 2023. "An amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41748-y
    DOI: 10.1038/s41467-023-41748-y
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    References listed on IDEAS

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    1. Parisa Hosseinzadeh & Paris R. Watson & Timothy W. Craven & Xinting Li & Stephen Rettie & Fátima Pardo-Avila & Asim K. Bera & Vikram Khipple Mulligan & Peilong Lu & Alexander S. Ford & Brian D. Weitzn, 2021. "Anchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Vijaya R. Pattabiraman & Jeffrey W. Bode, 2011. "Rethinking amide bond synthesis," Nature, Nature, vol. 480(7378), pages 471-479, December.
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