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首页> 外文期刊>Molecular cancer therapeutics >Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies
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Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

机译：通过高度特异性骆驼衍生的抗体有效抑制骨形态发生蛋白功能

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Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 non-canonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4(+) malignancies. (C) 2015 AACR.
机译：骨形态发生蛋白（BMP）在组织稳态和疾病中具有重要但不同的作用，包括致癌物和肿瘤进展。大量的BMP抑制剂可用于研究BMP功能;然而，由于大多数这些拮抗剂是混杂的，评估单个BMP的特定效果是不可行的。因为不同BMP的致癌作用因每个肿瘤而变化，所以需要高选择性的BMP抑制剂。在这里，我们描述了三种类型的Llama衍生的重链可变结构域（VHH），其选择性地结合BMP4，BMP2和4，或BMP2,4,5和6.这些产生的VHHs对其具有很高的亲和力他们的目标并能够抑制BMP信令。表位融合和对接模型将光线放在BMP特异性的基础上。与天然抑制剂的宽结构覆盖相反，这些小分子靶向受体结合所涉及的BMP的凹槽和袋。在有机体实验中，BMP4的特异性抑制不影响正常干细胞的活化。此外，体外抑制癌症衍生的BMP4非规范信号导致结直肠癌细胞系中的化学敏感性增加。因此，由于它们具有高特异性和低的偏移效应，这些VHHS可以代表BMP4（+）恶性肿瘤的治疗替代品。 （c）2015年AACR。

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