A Protein Transduction Domain with Cell Uptake and Selectivity Profiles that Are Controlled by Multivalency Effects

SummaryProtein transduction domains (PTDs) are reagents that facilitate the delivery of diverse cargo to the interior of mammalian cells. We identified a PTD called “Ypep” (N-YTFGLKTSFNVQ-C), with cell penetration selectivity and potency profiles that are tightly controlled by multivalency effects. Pentavalent display of Ypep on M13 bacteriophage enables selective uptake of this phage in PC-3 human prostate cancer cells at low picomolar concentration and in the presence of human blood. All Ypep-dependent delivery is nontoxic and proceeds through energy-dependent endocytosis. Collectively, our results establish Ypep-displaying phage as a cell-penetrating platform with selectivity and potency profiles that compare to, or exceed, antibodies and their fragments. Our findings may have broader implications on the design of PTD technologies generated from phage display, as well as the use of Ypep-displaying phage as a prostate cancer cell-selective delivery platform