Tuning the Binding Affinity and Selectivity of Perfluoroaryl-Stapled Peptides by Cysteine-Editing.
Tuning the Binding Affinity and Selectivity of Perfluoroaryl-Stapled Peptides by Cysteine-Editing.
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DOI：
10.1002/chem.201804163
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发表时间：
2018-11
期刊：
影响因子：
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通讯作者：
S. Verhoork;Claire E. Jennings;Neshat Rozatian;J. Reeks;Jieman Meng;Emily K. Corlett;Fazila Bunglawala;M. Noble;Andrew G. Leach;Christopher R. Coxon
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文献类型：
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作者：
S. Verhoork;Claire E. Jennings;Neshat Rozatian;J. Reeks;Jieman Meng;Emily K. Corlett;Fazila Bunglawala;M. Noble;Andrew G. Leach;Christopher R. Coxon
越来越多的利用半胱氨酸交联将 α-螺旋肽“固定”成生物活性构象的方法正在出现。在此，探索了以不同立体化学、侧链长度和β-碳取代组合的“半胱氨酸类似物”替代L-半胱氨酸，以检查含硫醇残基对经过充分探索的模型系统p53-MDM2/MDMX中靶蛋白结合亲和力的影响，该模型系统由抑癌蛋白p53与调节p53活性的蛋白MDM2和MDMX相互作用构成。在一些情况下，一个或多个L-半胱氨酸残基的替换使所测量的肽的结合亲和力和靶标选择性发生显着变化。计算构建的同源模型表明，一些修饰，例如合并两个 d-半胱氨酸残基，有利地改变关键功能氨基酸侧链的位置，这可能导致结合亲和力的变化，与测量的表面等离振子共振数据一致。
A growing number of approaches to "staple" α-helical peptides into a bioactive conformation using cysteine cross-linking are emerging. Here, the replacement of l-cysteine with "cysteine analogues" in combinations of different stereochemistry, side chain length and beta-carbon substitution, is explored to examine the influence that the thiol-containing residue(s) has on target protein binding affinity in a well-explored model system, p53-MDM2/MDMX, which is constituted by the interaction of the tumour suppressor protein p53 and proteins MDM2 and MDMX, which regulate p53 activity. In some cases, replacement of one or more l-cysteine residues afforded significant changes in the measured binding affinity and target selectivity of the peptide. Computationally constructed homology models indicate that some modifications, such as incorporating two d-cysteine residues, favourably alter the positions of key functional amino acid side chains, which is likely to cause changes in binding affinity, in agreement with measured surface plasmon resonance data.