De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist

被引:10
|
作者
Komatsu, Yamato [1 ]
Terasaka, Naohiro [1 ]
Sakai, Katsuya [2 ,3 ]
Mihara, Emiko [4 ]
Wakabayashi, Risa [1 ]
Matsumoto, Kunio [2 ,3 ]
Hilvert, Donald [5 ]
Takagi, Junichi [4 ]
Suga, Hiroaki [1 ]
机构
[1] Univ Tokyo, Grad Sch Sci, Dept Chem, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan
[2] Kanazawa Univ, Canc Res Inst, Div Tumor Dynam & Regulat, Kanazawa, Ishikawa 9201192, Japan
[3] Kanazawa Univ, WPI Nano Life Sci Inst WPI NanoLSI, Kanazawa, Ishikawa 9201192, Japan
[4] Osaka Univ, Inst Prot Res, Lab Prot Synth & Express, 3-2 Yamadaoka, Suita, Osaka 5650871, Japan
[5] Swiss Fed Inst Technol, Lab Organ Chem, CH-8093 Zurich, Switzerland
关键词
LUMAZINE SYNTHASE; IN-VITRO; PROTEIN; SELECTION; DISPLAY;
D O I
10.1016/j.isci.2021.103302
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Lasso-grafting (LG) technology is a method for generating de novo biologics (neo-biologics)by genetically implanting macrocyclic peptide pharmacophores, which are selected in vitro against a protein of interest, into loops of arbitrary protein scaffolds. In this study, we have generated a neo-capsid that potently binds the hepatocyte growth factor receptor MET by LG of anti-MET peptide pharmaco-phores into a circularly permuted variant of Aquifex aeolicus lumazine synthase(AaLS), a self-assembling protein nanocapsule. By virtue of displaying multiple-pharmacophores on its surface, the neo-capsid can induce dimerization (or multimerization)of MET, resulting in phosphorylation and endosomal internalization of the MET-capsid complex. This work demonstrates the potential of the LG technologyas a synthetic biology approach for generating capsid-based neobiologics capable of activating signaling receptors.
引用
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页数:13
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