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

ABSTRACT: 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.

SUBMITTER: Mogaki R

PROVIDER: S-EPMC5489047 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Mogaki Rina R Okuro Kou K Aida Takuzo T

Chemical science 20150318 5

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 ...[more]

PMID: 28706668

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