Article ; Online: MET-Activating Ubiquitin Multimers.
Angewandte Chemie (International ed. in English)
2023 Volume 62, Issue 36, Page(s) e202307157
Abstract: Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte growth factor (HGF) receptor, known as MET, plays an important role in tissue ... ...
Abstract | Receptor tyrosine kinases (RTKs) are generally activated through their dimerization and/or oligomerization induced by their cognate ligands, and one such RTK hepatocyte growth factor (HGF) receptor, known as MET, plays an important role in tissue regeneration. Here we show the development of ubiquitin (Ub)-based protein ligand multimers, referred to as U-bodies, which act as surrogate agonists for MET and are derived from MET-binding macrocyclic peptides. Monomeric Ub constructs (U-body) were first generated by genetic implantation of a macrocyclic peptide pharmacophore into a structural loop of Ub (lasso-grafting) and subsequent optimization of its flanking spacer sequences via mRNA display. Such U-body constructs exhibit potent binding affinity to MET, thermal stability, and proteolytic stability. The U-body constructs also partially/fully inhibited or enhanced HGF-induced MET-phosphorylation. Their multimerization to dimeric, tetrameric, and octameric U-bodies linked by an appropriate peptide linker yielded potent MET activation activity and downstream cell proliferation-promoting activity. This work suggests that lasso-grafting of macrocycles to Ub is an effective approach to devising protein-based artificial RTK agonists and it can be useful in the development of a new class of biologics for various therapeutic applications. |
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MeSH term(s) | Hepatocyte Growth Factor/metabolism ; Ubiquitin/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-met/metabolism ; Phosphorylation ; Peptides/pharmacology ; Peptides/metabolism |
Chemical Substances | Hepatocyte Growth Factor (67256-21-7) ; Ubiquitin ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Peptides |
Language | English |
Publishing date | 2023-07-31 |
Publishing country | Germany |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 2011836-3 |
ISSN | 1521-3773 ; 1433-7851 |
ISSN (online) | 1521-3773 |
ISSN | 1433-7851 |
DOI | 10.1002/anie.202307157 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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