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Publication 162  

  1. Sense-and-release Logic-gated Molecular Network Responding to Dimeric Cell Surface Proteins
    S. Angerani, N. Winssinger
    J. Am. Chem. Soc. 2020, 142, 12333-12340

Dimeric proteins are prominent in biology and receptor dimerization (homo- or hetero-dimerization) 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 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.

DOI: 10.1021/jacs.0c04469 

open archive unige:138561