De novo peptide grafting to a self-assembling nanocapsule yields a hepatocyte growth factor receptor agonist

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.