Hypoxia-Inducible\nFactor-1α-Activated Protein\nSwitch Based on Allosteric Self-Splicing Reduces Nonspecific Cytotoxicity\nof Pharmaceutical Drugs

Protein-based therapeutic agents currently used for targeted\ntumor\ntherapy exhibit limited penetrability, nonspecific toxicity, and a\nshort circulation half-life. Although targeting cell surface receptors\nimproves cancer selectivity, the receptors are also slightly expressed\nin normal cells; consequently, the nonspecific toxicity of recombinant\nprotein-based therapeutic agents has not been eliminated. In this\nstudy, an allosteric-regulated protein switch was designed that achieved\ncytoplasmic reorganization of engineered immunotoxins in tumor cells\nvia interactions between allosteric self-splicing elements and cancer\nmarkers. It can target the accumulated HIF-1α in hypoxic cancer\ncells and undergo allosteric activation, and the splicing products\nwere present in hypoxic cancer cells but were absent in normoxic cells,\nselectively killing tumor cells and reducing nonspecific toxicity\nto normal cells. The engineered pro-protein provides a platform for\ntargeted therapy of tumors while offering a novel universal strategy\nfor combining the activation of therapeutic functions with specific\ncancer markers. The allosteric self-splicing element is a powerful\ntool that significantly reduces the nonspecific cytotoxicity of therapeutic\nproteins.