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Taspase 1 is a unique protease not only pivotal for embryonic development but also implicated in leukemias and solid tumors. As such, this enzyme is a promising while still challenging therapeutic target, and with its protein structure featuring a flexible loop preceding the active site a versatile model system for drug development. Supramolecular ligands provide a promising complementary approach to traditional small‐molecule inhibitors. Recently, the multivalent arrangement of molecular tweezers allowed the successful targeting of Taspase 1's surface loop. With this study we now want to take the next logic step und utilize functional linker systems that not only allow the implementation of novel properties but also engage in protein surface binding. Consequently, we chose two different linker types differing from the original divalent assembly: a backbone with aggregation‐induced emission (AIE) properties to enable monitoring of binding and a calix[4]arene scaffold initially pre‐positioning the supramolecular binding units. With a series of four AIE‐equipped ligands with stepwise increased valency we demonstrated that the functionalized AIE linkers approach ligand binding affinities in the nanomolar range and allow efficient proteolytic inhibition of Taspase 1. Moreover, implementation of the calix[4]arene backbone further enhanced the ligands' inhibitory potential, pointing to a specific linker contribution. [ABSTRACT FROM AUTHOR]

This article, titled "Functional Linkers Support Targeting of Multivalent Tweezers to Taspase1," discusses the use of supramolecular binding units to specifically dock novel linker systems onto the target protease Taspase1. The researchers connected molecular tweezers with aggregation-induced emission (AIE) functionalities to create spider-like inhibitors that light up when they bind to the protein. They also utilized a calix[4]arene backbone to create a scorpion-like double pincer ligand with even better binding and enzyme inhibition properties. The full research article provides more detailed information on this topic. [Extracted from the article]