Rerouting the hypoxic response of cells by an artificial chemical transducer

All organisms are wired to respond to environmental fluctuations and signals in a specific manner, controlled by tightly regulated signal transduction pathways. Defects in the interactome and regulation of signaling pathways are the causes of many common diseases, such as cancer, neurodegenerative conditions and more. Thus, signal transduction poses an important therapeutic target for treatment of various conditions. To date, most attempts to manipulate signaling pathways have been done either by directly targeting single proteins or by genetically altering interacting partners. Recently, our group has introduced chemical transducers as new means for constructing novel communication networks, creating artificial communication in vitro between two unrelated proteins - Glutathione S-transferase (GST) and the platelet-derived growth factor (PDGF)1. The results encouraged us to develop a new generation of chemical transducers able to function in living cells free of genomic interference. We designed a chemical transducer for constructing unnatural communication between two unrelated proteins, Glycogen Synthase Kinase 3 (GSK-3) and Lactate Dehydrogenase A (LDHA). The newly synthesized molecule will allow control of GSK-3 activity by acute regulation of LDHA cell concentration in response to hypoxia and effect disease states involving the two protein targets.