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Computational Design, Combinatorial Screening and Experimental Analysis of Lung Cancer EGFRVIII-Binding Peptides

表皮生长因子受体 化学 肽库 虚拟筛选 靶向治疗 计算生物学 癌症 癌症研究 生物化学 生物 受体 药物发现 肽序列 遗传学 基因
作者
Dongyun Gao,Jun Yao,Xuefeng Zhou,Xia Zhang,Linlin Zhou,Qiangrong Wang,Shan Li,Xi Ding
出处
期刊:Journal of computational biophysics and chemistry [World Scientific]
卷期号:23 (02): 175-188
标识
DOI:10.1142/s2737416523500576
摘要

Human epidermal growth factor receptor mutation variant III ([Formula: see text] is a cancer-specific cell surface oncogenic marker and has been observed to be widely involved in the formation, progression and metastasis of lung cancer and some other tumors. Previously, a massive quantity of [Formula: see text]-binding peptides were enriched via random phage display (RPD) targeted against the protein. In this study, we reported rational discovery of 12-mer peptides with high affinity to [Formula: see text] and strong selectivity for [Formula: see text] over wild-type EGFR ([Formula: see text]. A combinatorial peptide library was designed to target [Formula: see text] based on over ten thousands of known [Formula: see text] binders enriched from RPD analysis, and a virtual high-throughput screening protocol was then systematically performed against the library to derive those potential candidates, which were further examined rigorously at structural and energetic levels to identify few promising hits. Anisotropy binding assays were carried out to substantiate the computational findings. Consequently, eight 12-mer peptides were designed as effective binders that can target the [Formula: see text] extracellular subdomain 3 (SD3). In particular, two potent peptides (T1: FLHRYEIVTSYF and T3: FLQKYEWNTSYW) were found to have a high affinity to [Formula: see text] and a good selectivity for [Formula: see text] over [Formula: see text]. Structural analysis revealed that the peptide-binding site can be divided into hydrophobic, polar and mixed regions, which correspond to the nonpolar [Formula: see text]-terminal section, polar/charged middle section and hybrid C-terminal section of the peptide. The peptide selectivity originated from the middle section, which can form a different hydrogen bond network between the two proteins upon the mutating perturbation, whereas the N- and C-terminal sections are primarily responsible for the peptide stability but not specificity.
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