Synthesis and stability studies of constrained peptide–antimony bicycles

Sven Ullrich; Pritha Ghosh; Minghao Shang; Sauhta Siryer; Santhanalaxmi Kumaresan; Bishvanwesha Panda; Lani J. Davies; Upamali Somathilake; Abhishek P. Patel; Christoph Nitsche

doi:10.1071/CH24094

RESEARCH ARTICLE (Open Access)

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Synthesis and stability studies of constrained peptide–antimony bicycles

Sven Ullrich

^A ^# , Pritha Ghosh ^A ^# , Minghao Shang ^A , Sauhta Siryer ^A , Santhanalaxmi Kumaresan ^A , Bishvanwesha Panda ^A , Lani J. Davies ^A , Upamali Somathilake ^A , Abhishek P. Patel ^A and Christoph Nitsche

^A ^*

+ Author Affiliations

- Author Affiliations

^A Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia.

^* Correspondence to: christoph.nitsche@anu.edu.au

^# These authors contributed equally and share first authorship.

Handling Editor: Curt Wentrup

Australian Journal of Chemistry 77, CH24094 https://doi.org/10.1071/CH24094

Submitted: 1 July 2024 Accepted: 5 August 2024 Published online: 27 August 2024

© 2024 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)

Abstract

Peptide therapeutics play an increasingly important role in modern drug discovery. Improving the pharmacokinetic profile of bioactive peptides has been effectively achieved with chemical modifications, especially macrocyclisation reactions. Consequently, there is a great demand for highly constrained compounds such as bicyclic peptides. In our previous research, we introduced peptide–bismuth bicycles and peptide–arsenic bicycles as new classes of constrained peptides. In this work, we extend our peptide bicyclisation strategy towards antimony. Similar to arsenic and bismuth, antimony(III) selectively binds to three cysteine residues in peptides, enabling the in situ formation of stable bicycles. The bicyclisation reaction occurs instantaneously under biocompatible conditions at physiological pH. Antimony–peptide bicycles remain largely intact in the presence of the common metal chelator ethylenediaminetetraacetic acid (EDTA) and the main endogenous thiol competitor glutathione (GSH). Furthermore, when challenged with bismuth(III) from water-soluble gastrodenol (bismuth tripotassium dicitrate), antimony–peptide bicycles convert into the corresponding bismuth–peptide bicycle, highlighting the superior thiophilicity of bismuth over other pnictogens. Our study further expands the toolbox of peptide multicyclisation with main group elements previously underexplored in chemical biology.

Keywords: antimony, bicycles, bismuth, cyclisation, cysteine, macrocycles, peptides, pnictogens.

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