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.
Here, we report ribosomal
construction of thioether-macrocyclic
α/β3-peptide libraries in which β-homoglycine,
β-homoalanine, β-homophenylglycine, and β-homoglutamine
are introduced by genetic code reprogramming. The libraries were applied
to the RaPID (Random nonstandard Peptides Integrated Discovery) selection
against human EGFR to obtain PPI (protein–protein interaction)
inhibitors. The resulting peptides contained up to five β3-amino acid (β3AA) residues and exhibited
outstanding binding affinity, PPI inhibitory activity, and proteolytic
stability, which were attributed to the β3AAs included
in the peptides. This showcase work has demonstrated that the use
of such β3AAs enhances the drug-like properties of
peptides, providing a unique platform for the discovery of de novo
macrocycles against a protein of interest.
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