文章基本信息

标题：De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist
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作者：Yamato Komatsu ; Naohiro Terasaka ; Katsuya Sakai 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：11
页码：1-13
DOI：10.1016/j.isci.2021.103302
语种：English
出版社：Elsevier
摘要：SummaryLasso-grafting (LG) technology is a method for generatingde novobiologics (neobiologics) by genetically implanting macrocyclic peptide pharmacophores, which are selectedin vitroagainst 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 pharmacophores into a circularly permuted variant ofAquifex aeolicuslumazine 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 technology as a synthetic biology approach for generating capsid-based neobiologics capable of activating signaling receptors.Graphical abstractDisplay OmittedHighlights•Lasso-grafting enabled multiple display of peptide pharmacophore on protein capsid•Engineered capsids induced dimerization of MET resulting in phosphorylation•Engineered capsids were internalized into endosome via MET phosphorylationPeptides; Biotechnology; Synthetic biology