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Chem Sci. 2015 May 1;6(5):2802-2805. doi: 10.1039/c5sc00524h. Epub 2015 Mar 18.

Molecular glues for manipulating enzymes: trypsin inhibition by benzamidine-conjugated molecular glues.

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Department of Chemistry and Biotechnology , School of Engineering , The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku , Tokyo 113-8656 , Japan . Email: ; Email: ; Tel: +81-3-5841-7251.
RIKEN Center for Emergent Matter Science , 2-1 Hirosawa , Wako , Saitama 351-0198 , Japan.


Water-soluble bioadhesive polymers bearing multiple guanidinium ion (Gu+) pendants at their side-chain termini (Glue n -BA, n = 10 and 29) that were conjugated with benzamidine (BA) as a trypsin inhibitor were developed. The Glue n -BA molecules are supposed to adhere to oxyanionic regions of the trypsin surface, even in buffer, via a multivalent Gu+/oxyanion salt-bridge interaction, such that their BA group properly blocks the substrate-binding site. In fact, Glue10-BA and Glue29-BA exhibited 35- and 200-fold higher affinities for trypsin, respectively, than a BA derivative without the glue moiety (TEG-BA). Most importantly, Glue10-BA inhibited the protease activity of trypsin 13-fold more than TEG-BA. In sharp contrast, m Glue27-BA, which bears 27 Gu+ units along the main chain and has a 5-fold higher affinity than TEG-BA for trypsin, was inferior even to TEG-BA for trypsin inhibition.

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