Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo náměstí 2, 16610, Praha 6, Czech Republic.
ChemMedChem. 2022 Aug 3;17(15):e202200152. doi: 10.1002/cmdc.202200152. Epub 2022 May 24.
A rationally-designed scaffold of cyclic octapeptides composed of two units of the natural tripeptide glutathione (GSH) was optimized to strongly and selectively capture toxic lead ions (Pb(II)). Using state-of-the-art computational tools, a list of eleven plausible peptides was shortened to five analogs based on their calculated affinity to Pb(II) ions. We then synthesized and investigated them for their abilities to recover Pb-poisoned human cells. A clear pattern was observed from the in vitro detoxification results, indicating the importance of cavity size and polar moieties to enhance metal capturing. These, together with the apparent benefit of cyclizing the peptides, improved the detoxification of the two lead peptides by approximately two folds compared to GSH and the benchmark chelating agents against Pb poisoning. Moreover, the two peptides did not show any toxicity and, therefore, were thoroughly investigated to determine their potential as next-generation remedies for Pb poisoning.
合理设计的由两个天然三肽谷胱甘肽（GSH）单元组成的环状八肽支架被优化为能够强烈和选择性地捕获有毒的铅离子（Pb（II））。使用最先进的计算工具，根据它们对 Pb（II）离子的计算亲和力，将十一个可能的肽列表缩短到五个类似物。然后，我们合成并研究了它们回收 Pb 中毒人类细胞的能力。从体外解毒结果中观察到一个明显的模式，表明空腔大小和极性部分对于增强金属捕获很重要。这些，再加上环化肽的明显好处，使两种铅肽的解毒能力比 GSH 和针对 Pb 中毒的基准螯合剂提高了约两倍。此外，这两种肽没有显示出任何毒性，因此，对它们进行了深入研究，以确定它们作为下一代 Pb 中毒治疗方法的潜力。
