Cyclic Peptide-Based Biologics Regulating HGF-MET.
Cyclic Peptide-Based Biologics Regulating HGF-MET.
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DOI：
10.3390/ijms21217977
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发表时间：
2020-10-27
影响因子：
5.6
通讯作者：
Sakai K
中科院分区：
文献类型：
--
作者：
Sato H;Imamura R;Suga H;Matsumoto K;Sakai K
使用随机非标准肽集成发现系统，我们获得了与肝细胞生长因子（HGF）或间充质-上皮转化因子结合的环肽。(MET)HGF抑制肽-8（HiP-8）选择性结合双链活性HGF，但不结合单链前体HGF。HGF在原子力显微镜中显示其分子形状的动态变化，但HiP-8抑制分子形状的动态变化进入静态状态。HiP-8对HGF分子动力学的抑制与结合MET能力的丧失有关。HiP-8可选择性地检测癌组织中的活性HGF，并且由HiP-8探测的活性HGF与活化的MET显示共定位。使用HiP-8，可以通过正电子发射断层扫描检测具有活性HGF的癌组织。HiP-8似乎适用于癌症的诊断和治疗。相比之下，基于受体二聚化作为活化的必要过程，与MET的胞外区结合的环肽的交联成功地产生了MET的人工配体。合成的MET激动剂激活MET并表现出与HGF的作用难以区分的生物活性。由环肽组成的MET激动剂可以通过化学合成而不是重组蛋白表达来制造，因此有望成为适用于治疗和再生医学的新生物制剂。
Using a random non-standard peptide integrated discovery system, we obtained cyclic peptides that bind to hepatocyte growth factor (HGF) or mesenchymal-epithelial transition factor. (MET) HGF-inhibitory peptide-8 (HiP-8) selectively bound to two-chain active HGF, but not to single-chain precursor HGF. HGF showed a dynamic change in its molecular shape in atomic force microscopy, but HiP-8 inhibited dynamic change in the molecular shape into a static status. The inhibition of the molecular dynamics of HGF by HiP-8 was associated with the loss of the ability to bind MET. HiP-8 could selectively detect active HGF in cancer tissues, and active HGF probed by HiP-8 showed co-localization with activated MET. Using HiP-8, cancer tissues with active HGF could be detected by positron emission tomography. HiP-8 seems to be applicable for the diagnosis and treatment of cancers. In contrast, based on the receptor dimerization as an essential process for activation, the cross-linking of the cyclic peptides that bind to the extracellular region of MET successfully generated an artificial ligand to MET. The synthetic MET agonists activated MET and exhibited biological activities which were indistinguishable from the effects of HGF. MET agonists composed of cyclic peptides can be manufactured by chemical synthesis but not recombinant protein expression, and thus are expected to be new biologics that are applicable to therapeutics and regenerative medicine.
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影响因子：
3.7
作者：
Factor, Valentina M.;Seo, Daekwan;Thorgeirsson, Snorri S.
通讯作者：
Thorgeirsson, Snorri S.
影响因子：
16.6
作者：
Ito, Kenichiro;Sakai, Katsuya;Suzuki, Yoshinori;Ozawa, Naoya;Hatta, Tomohisa;Natsume, Tohru;Matsumoto, Kunio;Suga, Hiroaki
通讯作者：
Suga, Hiroaki
影响因子：
64.8
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
通讯作者：
Mazzone M
影响因子：
6
作者：
del Castillo, Gaelle;Factor, Valentina M.;Sanchez, Aranzazu
通讯作者：
Sanchez, Aranzazu
DOI：
10.1073/pnas.0403412101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Borowiak, M;Garratt, AN;Birchmeier, C
通讯作者：
Birchmeier, C