Enzyme-Instructed Supramolecular Assemblies Occlude Extrinsic Aquaporin-4 via Multivalent Effect for Sensitized Glioma Chemotherapy.

Aquaporin-4 (AQP4) proteins serve as a potential therapeutic target for glioma treatment while efficient small molecular inhibitors remain undiscovered. TGN-020 exhibits only transient inhibitory effects and lacks cell specificity. Stemmed from the solvent-exposed region of TGN-020, here we synthesized TGN-020/peptide conjugates which can self-assemble upon dephosphorylation. These conjugates selectively formed supramolecular nanofibers on the plasma membrane of ALP+/AQP4+ glioma cells, which bind to AQP4 in a multivalent manner. The AQP4-nanofiber interaction turned out to be a sustained inhibition and impeded the water exchange. The occlusion of AQP4 enhanced the sensitivity of glioma xenografts to temozolomide treatment in a subcutaneous mouse model. We envision that protein-assembly interactions represent a promising strategy for enabling multivalent binding to proteins of interest, which lead to the sustained regulation of protein function for potential biomedical applications.