受限肽锑双环的合成与稳定性研究

IF 1 4区 化学 Q4 CHEMISTRY, MULTIDISCIPLINARY Australian Journal of Chemistry Pub Date : 2024-08-27 DOI:10.1071/ch24094
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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引用次数: 0

摘要

多肽疗法在现代药物研发中发挥着越来越重要的作用。通过化学修饰,特别是大环化反应,可以有效改善生物活性肽的药代动力学特征。因此,对双环肽等高约束化合物的需求量很大。在之前的研究中,我们介绍了肽铋双环和肽砷双环这两类新的受约束肽。在这项工作中,我们将多肽双环化策略扩展到了锑。与砷和铋类似,锑(III)也能选择性地与肽中的三个半胱氨酸残基结合,从而在原位形成稳定的双环。在生理 pH 值的生物兼容条件下,双环化反应会瞬间发生。在常见金属螯合剂乙二胺四乙酸(EDTA)和主要内源性硫醇竞争者谷胱甘肽(GSH)的作用下,锑肽双环基本保持完好。此外,当受到水溶性胃登醇(铋三钾二枸橼酸盐)中的铋(III)的挑战时,锑肽自行车会转化为相应的铋肽自行车,这突出表明铋的亲硫性优于其他致幻剂。我们的研究进一步扩大了多肽多环化的工具箱,其中包含了以前在化学生物学中尚未充分探索的主族元素。
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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.

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来源期刊
Australian Journal of Chemistry
Australian Journal of Chemistry 化学-化学综合
CiteScore
2.50
自引率
0.00%
发文量
65
审稿时长
1.3 months
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.
期刊最新文献
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