Director of Chemistry Education
Seoul National University
Cell Penetrating Peptides to Increase Passive Permeability of Larger Cyclic Peptides as Inhibitors for Protein-Protein Interactions
Among developing drugs, the most promising new drug candidates may be targeting protein-protein interactions, PPIs, in cytosol space. Cyclic peptides are leading categorized compounds as inhibitors of PPIs for their structural rigidity and chemical stability. In order to inhibit efficiently, the cyclic peptides should be larger than conventional small molecule drugs to cover larger surface area of PPI. However, the larger candidate peptide to be, the less it permeable passively to get through cell membrane. 1
We have been developing novel cell penetrating peptides, CPPs 2 and investigating mechanisms. 3 One of our aims is to facilitate translocation of such large molecular weight PPI inhibitors that have intrinsically poor cell-permeability, when it compares with small molecules. As a proof of concept, we try to improve permeability of cyclosporine A, CsA, which has been known to inhibit a variety of intracellular PPIs through its unusual conformation-dependent passive permeability. By simply mixing CsA with our amphipathic CPPs, the drug is passing through membrane with higher diffusion coefficient measured by the parallel artificial membrane permeability assay, PAMPA.
Furthermore, a dose of the drug is significantly reduced, efficiently inhibiting secretion of cytokines using T cell. In vivo animal model studies show that 1/100 amount of CsA with our CPP is enough for efficacy to compare with CsA alone. Results suggest that the combination of CsA and our CPPs is an alternative therapeutic against dry eye syndrome with alleviated side-effects. Taken together, our CPPs can be efficient tools to deliver PPI inhibiting peptide drug candidates whose molecular weight is larger than 1,000.
AuthorsSoonsil Hyun, Jane Cho, Jaehoon Yu
AffiliationsDepartment of Chemistry & Education, Seoul National University, Seoul 151-742, Korea
1. Pye CR et al., J. Med. Chem., 2017, 60, 1665
2. Jang SM et al., Angew. Chem. Int. Ed. Engl., 2014, 53, 10086
3. Hyun S et al., ACS Cent. Sci., 2018, 4, 885