ArticleNature biomedical engineering2023
Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions.
Article in Nature biomedical engineering, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed, 16 citations in OpenAlex.
- DNA-programmed bispecific peptide assemblies for delivering cytotoxic payload to cells expressing EGFR and MET receptors.RSC chemical biology · 2026Article
- MET Enhances Amivantamab Binding to EGFR and Antibody-Dependent Cellular Toxicity.Cancer science · 2026Article
- Article
- Considerations for the genotoxicity assessment of middle size peptide drugs containing non-canonical amino acid residues.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2023Article
- Lasso-grafted designer cytokines.Nature biomedical engineering · 2023Article
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15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Short half-lives in circulation and poor transport across the blood-brain barrier limit the utility of cytokines and growth factors acting as receptor agonists. Here we show that surrogate receptor agonists with longer half-lives in circulation and enhanced transport rates across the blood-brain barrier can be generated by genetically inserting macrocyclic peptide pharmacophores into the structural loops of the fragment crystallizable (Fc) region of a human immunoglobulin. We used such 'lasso-grafting' approach, which preserves the expression levels of the Fc region and its affinity for the neonatal Fc receptor, to generate Fc-based protein scaffolds with macrocyclic peptides binding to the receptor tyrosine protein kinase Met. The Met agonists dimerized Met, inducing biological responses that were similar to those induced by its natural ligand. Moreover, lasso-grafting of the Fc region of the mouse anti-transferrin-receptor antibody with Met-binding macrocyclic peptides enhanced the accumulation of the resulting Met agonists in brain parenchyma in mice. Lasso-grafting may allow for designer protein therapeutics with enhanced stability and pharmacokinetics.
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