De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist
| Autor: | Katsuya Sakai, Naohiro Terasaka, Kunio Matsumoto, Donald Hilvert, Hiroaki Suga, Emiko Mihara, Risa Wakabayashi, Yamato Komatsu, Junichi Takagi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
Aquifex aeolicus Multidisciplinary biology Chemistry media_common.quotation_subject Science viruses Peptide biology.organism_classification Lumazine synthase Article Cell biology Hepatocyte Growth Factor Receptor biology.protein Phosphorylation Pharmacophore Internalization Receptor Peptides Synthetic biology media_common Biotechnology |
| Zdroj: | iScience, Vol 24, Iss 11, Pp 103302-(2021) iScience, 24 (11) iScience |
| DOI: | 10.3929/ethz-b-000520801 |
| Popis: | Summary Lasso-grafting (LG) technology is a method for generating de novo biologics (neobiologics) 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 pharmacophores 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 technology as a synthetic biology approach for generating capsid-based neobiologics capable of activating signaling receptors. Graphical abstract Highlights • 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 phosphorylation Peptides; Biotechnology; Synthetic biology |
| Databáze: | OpenAIRE |
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