It is estimated that ~80% of drug targets are beyond the reach of current drug modalities, namely small molecules and conventional biologics. Two prominent classes of “undruggable” targets are the proteins involved in intracellular protein-protein interactions (PPIs) and those that are missing/defective due to genetic mutations. We are developing intracellular biologics as next-generation therapeutics against previously undruggable targets by leveraging a family of cyclic cell-penetrating peptides (CPPs). These CPPs enter the mammalian cell by endocytosis and efficiently exit the endosome into the cytosol by a novel endosomal escape mechanism. They can deliver a wide variety of membrane-impermeable cargo molecules (e.g., peptides, proteins, and nucleic acids) into the mammalian cell cytosol with unprecedented efficiencies and exhibit excellent other “drug-like” properties. I will present examples of using cyclic CPPs to deliver peptides, proteins, and nucleic acids for potential treatment of human genetic diseases as well as diseases caused by aberrant intracellular PPIs (e.g., Keap1-Nrf2 and β-catenin-TCF interactions).

Generating intracellular biologics with cyclic cell-penetrating peptides

ACS Spring Meeting 2021

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