Sense-and-Release Logic-Gated Molecular Network Responding to Dimeric Cell Surface Proteins

This is the authors' abstract. We don't add key points for this paper.

Dimeric proteins are prominent in biology, and receptor dimerization (homo- or heterodimerization) is central to signal transduction. Herein, we report a network that responds to a membrane-associated dimeric protein with the uncaging of a powerful cytotoxic. The network is based on two ligands functionalized with peptide nucleic acids (PNAs) (templating strand and catalyst-functionalized strand, respectively) and a substrate with the caged cytotoxic (monomethyl auristatin E: MMAE; a high-affinity tubulin ligand). In the presence of the dimeric protein, the network yields a cooperative supramolecular assembly with a hybridization architecture that enhances the templated reaction and enables the uncaging of a substrate. The network was tested on cells that express a cancer biomarker, carbonic anhydrase IX, in response to hypoxia. The output of the network correlates with the expression of carbonic anhydrase IX, and this biomarker was harnessed to uncage a potent cytotoxic agent.