Bismuth-Selenopeptides Combine Potent Bioactivity with Exceptional Kinetic Inertness.

IF 16.9
Pritha Ghosh, Minghao Shang, Katarina Trajković, Lani J Davies, Upamali Somathilake, Toshiki Takei, Hironobu Hojo, Christoph Nitsche
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Abstract

Bismuth peptides and proteins are emerging as versatile tools for medicinal chemistry and chemical biology. Bismuth(III) binds three cysteine residues in peptides and proteins with remarkable selectivity. While the thermodynamic stability of these bismuth complexes is outstanding, their kinetic lability imposes limitations. Introducing bismuth selenopeptides, we demonstrate that selenocysteine binds bismuth with substantially higher kinetic stability than cysteine. This effect was quantified by directly comparing a peptide containing three cysteine residues with an identical peptide containing three selenocysteines. Bismuth selenopeptides are not only inert to strong chelators such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) but also to the natural metal-binding protein transferrin present in human plasma. We further demonstrate biological utility by developing bismuth selenopeptides that selectively bind and inhibit unrelated target proteins. To extend this concept to a more complex system, we investigated the human epidermal growth factor (EGF), a small protein comprising three disulfide bonds. We established that precisely two bismuth atoms bind to the six cysteine or selenocysteine residues in EGF and seleno-EGF, respectively. In the presence of EDTA, bismuth seleno-EGF remains fully intact, unlike its cysteine-based analog, consistent with observations from smaller peptides. Structural models confirm full preservation of the native EGF fold.

Abstract Image

铋-硒肽结合了强大的生物活性和特殊的动力学惰性。
铋肽和铋蛋白正在成为药物化学和化学生物学的多功能工具。铋(III)结合三个半胱氨酸残基在肽和蛋白质具有显著的选择性。虽然这些铋配合物的热力学稳定性是突出的,但它们的动力学不稳定性施加了限制。引入铋硒肽,我们证明硒半胱氨酸结合铋具有比半胱氨酸高得多的动力学稳定性。通过直接比较含有三个半胱氨酸残基的肽与含有三个硒代半胱氨酸的相同肽,可以量化这种效应。铋硒肽不仅对强螯合剂如乙二胺四乙酸(EDTA)和二乙烯三胺五乙酸(DTPA)惰性,而且对存在于人血浆中的天然金属结合蛋白转铁蛋白也惰性。我们进一步通过开发铋硒肽选择性结合和抑制不相关的靶蛋白来证明其生物实用性。为了将这一概念扩展到更复杂的系统,我们研究了人类表皮生长因子(EGF),一种由三个二硫键组成的小蛋白质。我们确定了两个铋原子分别与EGF和硒-EGF中的六个半胱氨酸或硒半胱氨酸残基结合。与基于半胱氨酸的类似物不同,在EDTA存在的情况下,铋硒egf保持完全完整,这与较小肽的观察结果一致。结构模型证实了原生EGF褶皱的完整保存。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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