High-Affinity Copolymers Inhibit Digestive Enzymes
by Surface Recognition
Patrick Gilles
Kirstin Wenck
Inga Stratmann
Michael Kirsch
Daniel A. Smolin
Torsten Schaller
Herbert de Groot
Arno Kraft
Thomas Schrader
10.1021/acs.biomac.7b00162.s001
https://acs.figshare.com/articles/journal_contribution/High-Affinity_Copolymers_Inhibit_Digestive_Enzymes_by_Surface_Recognition/4986647
This
account presents a general method for the construction of
polymeric surface binders for digestion enzymes. Two prominent parts,
namely, the modification of the copolymer composition and the screening
assay for the most powerful inhibitors are both amenable to parallelization.
The concept hinges on the appropriate selection of amino-acid-selective
comonomers, their free radical copolymerization, and subsequent screening
of the resulting copolymer library for efficient enzyme inhibition.
A microscale synthetic procedure for the copolymerization process
was developed, which produces water-soluble affinity polymers that
can be stored for years at room temperature. Initial parallel screening
was conducted in standard enzyme assays to identify polymeric inhibitors,
which were subsequently subjected to determination of IC<sub>50</sub> values for their target enzyme. For all digestion enzymes, except
elastase, a number of polymer inhibitors were found, some of which
were selective toward one or two protein targets. Since the key monomers
of the best inhibitors bind to amino acid residues in the direct vicinity
of the active site, we conclude that efficient coverage of the immediate
environment by the copolymers is critical. Strong interference with
enzymatic activity is brought about by blocking the substrate access
and product exit to and from the active site.
2017-04-18 00:00:00
screening
digestion enzymes
assay
High-Affinity Copolymers Inhibit Digestive Enzymes
IC 50 values
copolymerization
inhibitor
site
copolymer