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Rational Optimization of Tumor Suppressor-Derived Peptide Inhibitor Selectivity between Oncogene Tyrosine Kinases ErbB1 and ErbB2
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2017-11-13 , DOI: 10.1002/ardp.201700181 Yilin Deng 1 , Jian Li 2
Archiv der Pharmazie ( IF 4.3 ) Pub Date : 2017-11-13 , DOI: 10.1002/ardp.201700181 Yilin Deng 1 , Jian Li 2
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The tumor‐suppressor protein Mig‐6 has been found to directly target and inhibit the human ErbB receptor tyrosine kinases ErbB1 and ErbB2. Despite their highly homologous nature, these two kinases are separately involved in the development of different types of human cancer. Here, we utilized a rational strategy to iteratively optimize the interaction specificity of the two kinases with a Mig‐6 derived peptide by exploiting structural diversity space. Instead of traditionally improving the peptide binding potency, the optimization attempts to maximize the affinity difference between peptides binding to ErbB1 and ErbB2. The computational design was also substantiated by using fluorescence‐based assays. Consequently, we successfully designed three peptides, HSLTPTQSF, THLMNLLRI, and NSGCPMHK, with high or moderate selectivity for ErbB1 over ErbB2 (3.1‐, 6.3‐, and 3.0‐fold, respectively) and two peptides, PCMTDFLFT and WVIFPSQTN, with moderate or modest selectivity for ErbB2 over ErbB1 (3.5‐ and 1.6‐fold, respectively). The method is expected to be used for the rational molecular design of selective peptide entities for other protein systems.
中文翻译：
癌基因酪氨酸激酶 ErbB1 和 ErbB2 之间抑癌肽抑制剂选择性的合理优化
已发现肿瘤抑制蛋白 Mig-6 直接靶向并抑制人类 ErbB 受体酪氨酸激酶 ErbB1 和 ErbB2。尽管它们具有高度同源性，但这两种激酶分别参与了不同类型人类癌症的发展。在这里，我们利用一种合理的策略，通过利用结构多样性空间来迭代优化两种激酶与 Mig-6 衍生肽的相互作用特异性。与传统上提高肽结合效力不同，优化尝试最大化与 ErbB1 和 ErbB2 结合的肽之间的亲和力差异。计算设计也通过使用基于荧光的测定得到证实。因此，我们成功设计了三种肽，HSLTPTQSF、THLMNLLRI 和 NSGCPMHK，它们对 ErbB1 的选择性高或中度高于 ErbB2 (3. 1 倍、6.3 倍和 3.0 倍）和两种肽，PCMTDFLFT 和 WVIFPSQTN，对 ErbB2 的选择性比 ErbB1 具有中等或中等（分别为 3.5 倍和 1.6 倍）。该方法有望用于其他蛋白质系统的选择性肽实体的合理分子设计。
更新日期：2017-11-13
中文翻译：
癌基因酪氨酸激酶 ErbB1 和 ErbB2 之间抑癌肽抑制剂选择性的合理优化
已发现肿瘤抑制蛋白 Mig-6 直接靶向并抑制人类 ErbB 受体酪氨酸激酶 ErbB1 和 ErbB2。尽管它们具有高度同源性，但这两种激酶分别参与了不同类型人类癌症的发展。在这里，我们利用一种合理的策略，通过利用结构多样性空间来迭代优化两种激酶与 Mig-6 衍生肽的相互作用特异性。与传统上提高肽结合效力不同，优化尝试最大化与 ErbB1 和 ErbB2 结合的肽之间的亲和力差异。计算设计也通过使用基于荧光的测定得到证实。因此，我们成功设计了三种肽，HSLTPTQSF、THLMNLLRI 和 NSGCPMHK，它们对 ErbB1 的选择性高或中度高于 ErbB2 (3. 1 倍、6.3 倍和 3.0 倍）和两种肽，PCMTDFLFT 和 WVIFPSQTN，对 ErbB2 的选择性比 ErbB1 具有中等或中等（分别为 3.5 倍和 1.6 倍）。该方法有望用于其他蛋白质系统的选择性肽实体的合理分子设计。
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