Sven Ullrich, Pritha Ghosh, Minghao Shang, Sauhta Siryer, Santhanalaxmi Kumaresan, Bishvanwesha Panda, Lani J. Davies, Upamali Somathilake, Abhishek P. Patel, Christoph Nitsche
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Synthesis and stability studies of constrained peptide–antimony bicycles
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.
期刊介绍:
Australian Journal of Chemistry - an International Journal for Chemical Science publishes research papers from all fields of chemical science. Papers that are multidisciplinary or address new or emerging areas of chemistry are particularly encouraged. Thus, the scope is dynamic. It includes (but is not limited to) synthesis, structure, new materials, macromolecules and polymers, supramolecular chemistry, analytical and environmental chemistry, natural products, biological and medicinal chemistry, nanotechnology, and surface chemistry.
Australian Journal of Chemistry is published with the endorsement of the Commonwealth Scientific and Industrial Research Organisation (CSIRO) and the Australian Academy of Science.