Journal
ISCIENCE
Volume 24, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2021.103302
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Funding
- Japanese Society for the Promotion of Science (JSPS) [JP20H05618]
- Japan Agency for Medical Research and Development (AMED), Basis for Supporting Innovative Drug Discovery and Life Science Research [JP20am0101090]
- JSPS KAKENHI [20K06553, 19H03449]
- Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University
- Ministry of Education, Culture, Sports, Science and Technology of Japan [JPMXP09A20UT]
- Noguchi Institute
- Grants-in-Aid for Scientific Research [19H03449, 20K06553] Funding Source: KAKEN
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Lasso-grafting (LG) technology involves genetically implanting macrocyclic peptide pharmacophores into loops of arbitrary protein scaffolds to generate novel biologics. In this study, a neo-capsid that potently binds the hepatocyte growth factor receptor MET was created using this technology. This work demonstrates the potential of LG technology in generating capsid-based neobiologics capable of activating signaling receptors.
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.
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