Advancements in the Development of HIF-1α-Activated Protein Switches for Use in Enzyme Prodrug Therapy
These protein switches are composed of the prodrug-converting enzyme yeast cytosine deaminase (yCD), which converts the non-toxic prodrug 5-fluorocytosine (5FC) to the highly toxic chemotherapeutic 5-fluorouracil (5FU), and the HIF-1α-binding CH1 domain of the human p300 protein. The cancer marker, HIF-1α, modulates the enzymatic activity of the yCD-domain of the switch, either through an allosteric mechanism or through stabilizing the protein such that it accumulates at higher levels in the cell. In normal cells HIF-1α is absent and the yCD domain is inactive. In the presence of HIF-1α – ideally only in cancer cells – the yCD domain is active and able to produce the chemotherapeutic.