The Experts below are selected from a list of 1518 Experts worldwide ranked by ideXlab platform
Takuzo Aida - One of the best experts on this subject based on the ideXlab platform.
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molecular glue that spatiotemporally turns on protein protein interactIons
Journal of the American Chemical Society, 2019Co-Authors: Rina Mogaki, Kou Okuro, Ryosuke Ueki, Shinsuke Sando, Takuzo AidaAbstract:We developed a dendritic molecular glue PCGlue-NBD that can serve universally to "turn on" protein-protein interactIons (PPIs) spatiotemporally. PCGlue-NBD carrying multiple Guanidinium Ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regIons, thereby suppressing PPIs with their receptor proteins. Upon irradiatIon with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesIon is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migratIon, which can be made spatiotemporally with a millimeter-scale resolutIon by pointwise irradiatIon with UV light.
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Molecular Glue that Spatiotemporally Turns on Protein–Protein InteractIons
2019Co-Authors: Rina Mogaki, Kou Okuro, Ryosuke Ueki, Shinsuke Sando, Takuzo AidaAbstract:We developed a dendritic molecular glue PCGlue-NBD that can serve universally to “turn on” protein–protein interactIons (PPIs) spatiotemporally. PCGlue-NBD carrying multiple Guanidinium Ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regIons, thereby suppressing PPIs with their receptor proteins. Upon irradiatIon with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesIon is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migratIon, which can be made spatiotemporally with a millimeter-scale resolutIon by pointwise irradiatIon with UV light
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Caged Molecular Glues as Photoactivatable Tags for Nuclear TranslocatIon of Guests in Living Cells
2018Co-Authors: Akio Arisaka, Kou Okuro, Rina Mogaki, Takuzo AidaAbstract:We developed dendritic caged molecular glues (CagedGlue-R) as tags for nucleus-targeted drug delivery, whose multiple Guanidinium Ion (Gu+) pendants are protected by an anIonic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; BANVOC). Negatively charged CagedGlue-R hardly binds to anIonic biomolecules because of their electrostatic repulsIon. However, upon exposure of CagedGlue-R to UV light or near-infrared (NIR) light, the BANVOC groups of CagedGlue-R are rapidly detached to yield an uncaged molecular glue (UncagedGlue-R) that carries multiple Gu+ pendants. Because Gu+ forms a salt bridge with PO4–, UncagedGlue-R tightly adheres to anIonic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formatIon. When tagged with CagedGlue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the CagedGlue-R tag is photochemically uncaged to form UncagedGlue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with CagedGlue-R can be delivered efficiently to cell nuclei eventually by irradiatIon with light
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Guanidinium based molecular glues for modulatIon of biomolecular functIons
Chemical Society Reviews, 2017Co-Authors: Rina Mogaki, Kou Okuro, P K Hashim, Takuzo AidaAbstract:Molecular adhesIon based on multivalent interactIons plays essential roles in various biological processes. Hence, “molecular glues” that can adhere to biomolecules may modulate biomolecular functIons and therefore can be applied to therapeutics. This tutorial review describes design strategies for developing adhesive motifs for biomolecules based on multivalent interactIons. We highlight a Guanidinium Ion-based salt-bridge as a key interactIon for adhesIon to biomolecules and discuss the applicatIon of molecular glues for manipulatIon of biomolecular assemblies, drug delivery systems, and modulatIon of biomolecular functIons.
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FrictIon-Mediated Dynamic Disordering of Phospholipid Membrane by Mechanical MotIons of Photoresponsive Molecular Glue: ActivatIon of Ion PermeatIon
2016Co-Authors: Yushi Suzuki, Kou Okuro, Tadashi Takeuchi, Takuzo AidaAbstract:A water-soluble photoresponsive molecular glue, Azo-18Glue, consisting of a photochromic azobenzene core and two adhesive dendritic wedges with a total of 18 peripheral Guanidinium Ion (Gu+) pendants tightly adheres to the surface of a phospholipid membrane, even in buffer, via a multivalent salt-bridge formatIon with phosphate anIons. A photomechanical motIon of adhering Azo-18Glue possibly gives rise to dynamic structural disordering of the phospholipid membrane and activates transmembrane Ion permeatIon. In sharp contrast, no activatIon of Ion permeatIon results when poorly adhesive Azo-6Glue carrying only six Gu+ pendants is used in place of Azo-18Glue
Kou Okuro - One of the best experts on this subject based on the ideXlab platform.
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molecular glue that spatiotemporally turns on protein protein interactIons
Journal of the American Chemical Society, 2019Co-Authors: Rina Mogaki, Kou Okuro, Ryosuke Ueki, Shinsuke Sando, Takuzo AidaAbstract:We developed a dendritic molecular glue PCGlue-NBD that can serve universally to "turn on" protein-protein interactIons (PPIs) spatiotemporally. PCGlue-NBD carrying multiple Guanidinium Ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regIons, thereby suppressing PPIs with their receptor proteins. Upon irradiatIon with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesIon is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migratIon, which can be made spatiotemporally with a millimeter-scale resolutIon by pointwise irradiatIon with UV light.
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Molecular Glue that Spatiotemporally Turns on Protein–Protein InteractIons
2019Co-Authors: Rina Mogaki, Kou Okuro, Ryosuke Ueki, Shinsuke Sando, Takuzo AidaAbstract:We developed a dendritic molecular glue PCGlue-NBD that can serve universally to “turn on” protein–protein interactIons (PPIs) spatiotemporally. PCGlue-NBD carrying multiple Guanidinium Ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regIons, thereby suppressing PPIs with their receptor proteins. Upon irradiatIon with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesIon is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migratIon, which can be made spatiotemporally with a millimeter-scale resolutIon by pointwise irradiatIon with UV light
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Caged Molecular Glues as Photoactivatable Tags for Nuclear TranslocatIon of Guests in Living Cells
2018Co-Authors: Akio Arisaka, Kou Okuro, Rina Mogaki, Takuzo AidaAbstract:We developed dendritic caged molecular glues (CagedGlue-R) as tags for nucleus-targeted drug delivery, whose multiple Guanidinium Ion (Gu+) pendants are protected by an anIonic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; BANVOC). Negatively charged CagedGlue-R hardly binds to anIonic biomolecules because of their electrostatic repulsIon. However, upon exposure of CagedGlue-R to UV light or near-infrared (NIR) light, the BANVOC groups of CagedGlue-R are rapidly detached to yield an uncaged molecular glue (UncagedGlue-R) that carries multiple Gu+ pendants. Because Gu+ forms a salt bridge with PO4–, UncagedGlue-R tightly adheres to anIonic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formatIon. When tagged with CagedGlue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the CagedGlue-R tag is photochemically uncaged to form UncagedGlue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with CagedGlue-R can be delivered efficiently to cell nuclei eventually by irradiatIon with light
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Guanidinium based molecular glues for modulatIon of biomolecular functIons
Chemical Society Reviews, 2017Co-Authors: Rina Mogaki, Kou Okuro, P K Hashim, Takuzo AidaAbstract:Molecular adhesIon based on multivalent interactIons plays essential roles in various biological processes. Hence, “molecular glues” that can adhere to biomolecules may modulate biomolecular functIons and therefore can be applied to therapeutics. This tutorial review describes design strategies for developing adhesive motifs for biomolecules based on multivalent interactIons. We highlight a Guanidinium Ion-based salt-bridge as a key interactIon for adhesIon to biomolecules and discuss the applicatIon of molecular glues for manipulatIon of biomolecular assemblies, drug delivery systems, and modulatIon of biomolecular functIons.
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FrictIon-Mediated Dynamic Disordering of Phospholipid Membrane by Mechanical MotIons of Photoresponsive Molecular Glue: ActivatIon of Ion PermeatIon
2016Co-Authors: Yushi Suzuki, Kou Okuro, Tadashi Takeuchi, Takuzo AidaAbstract:A water-soluble photoresponsive molecular glue, Azo-18Glue, consisting of a photochromic azobenzene core and two adhesive dendritic wedges with a total of 18 peripheral Guanidinium Ion (Gu+) pendants tightly adheres to the surface of a phospholipid membrane, even in buffer, via a multivalent salt-bridge formatIon with phosphate anIons. A photomechanical motIon of adhering Azo-18Glue possibly gives rise to dynamic structural disordering of the phospholipid membrane and activates transmembrane Ion permeatIon. In sharp contrast, no activatIon of Ion permeatIon results when poorly adhesive Azo-6Glue carrying only six Gu+ pendants is used in place of Azo-18Glue
D Thirumalai - One of the best experts on this subject based on the ideXlab platform.
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interactIons between hydrophobic and Ionic solutes in aqueous Guanidinium chloride and urea solutIons lessons for protein denaturatIon mechanism
Journal of the American Chemical Society, 2007Co-Authors: Edward P Obrie, Ruxandra I Dima, Ernard R Ooks, D ThirumalaiAbstract:In order to clarify the mechanism of denaturant-induced unfolding of proteins we have calculated the interactIons between hydrophobic and Ionic species in aqueous Guanidinium chloride and urea solutIons using molecular dynamics simulatIons. Hydrophobic associatIon is not significantly changed in urea or Guanidinium chloride solutIons. The strength of interactIon between Ion pairs is greatly diminished by the Guanidinium Ion. Although the changes in electrostatic interactIons in urea are small, examinatIon of structures, using appropriate pair functIons, of urea and water around the solutes show strong hydrogen bonding between urea's carbonyl oxygen and the positively charged solute. Our results strongly suggest protein denaturatIon occurs by the direct interactIon model according to which the most commonly used denaturants unfold proteins by altering electrostatic interactIons either by solvating the charged residues or by engaging in hydrogen bonds with the protein backbone. To further validate the direct interactIon model we show that, in urea and Guanidinium chloride solutIons, unfolding of an unusually stable helix (H1) from mouse PrPC (residues 144-153) occurs by hydrogen bonding of denaturants to charged side chains and backbone carbonyl groups.
Michel Masella - One of the best experts on this subject based on the ideXlab platform.
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SolvatIon of the Guanidinium Ion in Pure Aqueous Environments: A Theoretical Study from an "Ab Initio"-Based Polarizable Force Field
Journal of Physical Chemistry B, 2017Co-Authors: Celine Houriez, Michael Meot-ner Mautner, Michel MasellaAbstract:We report simulatIon results regarding the hydratIon process of the Guanidinium catIon in water droplets and in bulk liquid water, at a low concentratIon of 0.03 M, performed using a polarizable approach to model both water/water and Ion/water interactIons. In line with earlier theoretical studies, our simulatIons show a preferential orientatIon of Guanidinium at water-vacuum interfaces, i.e., a parallel orientatIon of the Guanidinium plane to the aqueous surface. In an apparent contradictIon with earlier simulatIon studies, we show also that Guanidinium has a stronger propensity for the cores of aqueous systems than the ammonium catIon. However, our bulk simulatIon conditIons correspond to weaker catIon concentratIons than in earlier studies, by 2 orders of magnitude, and that the same simulatIons performed using a standard nonpolarizable force field leads to the same conclusIon. From droplet data, we extrapolate the Guanidinium single hydratIon enthalpy value to be -82.9 ± 2.2 kcal mol-1. That is about half as large as the sole experimental estimate reported to date, about -144 kcal mol-1. Our result yields a Guanidinium absolute bulk hydratIon free energy at ambiant conditIons to be -78.4 ± 2.6 kcal mol-1, a value smaller by 3 kcal mol-1 compared to ammonium. The relatively large magnitude of our Guanidinium hydratIon free energy estimate suggests the Gdm+ protein denaturing properties to result from a competitIon between the catIon hydratIon effects and the catIon/protein interactIons, a competitIon that can be modulated by weak differences in the protein or in the catIon chemical environment.
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SolvatIon of the Guanidinium Ion in Pure Aqueous Environments: A Theoretical Study from an “Ab Initio”-Based Polarizable Force Field
2017Co-Authors: Celine Houriez, Michael Meot-ner (mautner), Michel MasellaAbstract:We report simulatIon results regarding the hydratIon process of the Guanidinium catIon in water droplets and in bulk liquid water, at a low concentratIon of 0.03 M, performed using a polarizable approach to model both water/water and Ion/water interactIons. In line with earlier theoretical studies, our simulatIons show a preferential orientatIon of Guanidinium at water–vacuum interfaces, i.e., a parallel orientatIon of the Guanidinium plane to the aqueous surface. In an apparent contradictIon with earlier simulatIon studies, we show also that Guanidinium has a stronger propensity for the cores of aqueous systems than the ammonium catIon. However, our bulk simulatIon conditIons correspond to weaker catIon concentratIons than in earlier studies, by 2 orders of magnitude, and that the same simulatIons performed using a standard nonpolarizable force field leads to the same conclusIon. From droplet data, we extrapolate the Guanidinium single hydratIon enthalpy value to be −82.9 ± 2.2 kcal mol–1. That is about half as large as the sole experimental estimate reported to date, about −144 kcal mol–1. Our result yields a Guanidinium absolute bulk hydratIon free energy at ambiant conditIons to be −78.4 ± 2.6 kcal mol–1, a value smaller by 3 kcal mol–1 compared to ammonium. The relatively large magnitude of our Guanidinium hydratIon free energy estimate suggests the Gdm+ protein denaturing properties to result from a competitIon between the catIon hydratIon effects and the catIon/protein interactIons, a competitIon that can be modulated by weak differences in the protein or in the catIon chemical environment
Rina Mogaki - One of the best experts on this subject based on the ideXlab platform.
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molecular glue that spatiotemporally turns on protein protein interactIons
Journal of the American Chemical Society, 2019Co-Authors: Rina Mogaki, Kou Okuro, Ryosuke Ueki, Shinsuke Sando, Takuzo AidaAbstract:We developed a dendritic molecular glue PCGlue-NBD that can serve universally to "turn on" protein-protein interactIons (PPIs) spatiotemporally. PCGlue-NBD carrying multiple Guanidinium Ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regIons, thereby suppressing PPIs with their receptor proteins. Upon irradiatIon with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesIon is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migratIon, which can be made spatiotemporally with a millimeter-scale resolutIon by pointwise irradiatIon with UV light.
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Molecular Glue that Spatiotemporally Turns on Protein–Protein InteractIons
2019Co-Authors: Rina Mogaki, Kou Okuro, Ryosuke Ueki, Shinsuke Sando, Takuzo AidaAbstract:We developed a dendritic molecular glue PCGlue-NBD that can serve universally to “turn on” protein–protein interactIons (PPIs) spatiotemporally. PCGlue-NBD carrying multiple Guanidinium Ion (Gu+) pendants can adhere strongly to target proteins and cover their surfaces including the PPI interface regIons, thereby suppressing PPIs with their receptor proteins. Upon irradiatIon with UV light, PCGlue-NBD on a target protein is photocleaved at butyrate-substituted nitroveratryloxycarbonyl linkages in the dendrimer framework, so that the multivalency for the adhesIon is reduced. Consequently, the guest protein is liberated and becomes eligible for a PPI. We found that hepatocyte growth factor HGF, when mixed with PCGlue-NBD, lost the affinity toward its receptor c-Met. However, upon exposure of the PCGlue-NBD/HGF hybrid to light-emitting diode light (365 nm), the PCGlue-NBD molecules on HGF were photocleaved as described above, so that HGF was liberated and retrieved its intrinsic PPI affinity toward c-Met. The turn-on PPI, thus achieved for HGF and c-Met, leads to cell migratIon, which can be made spatiotemporally with a millimeter-scale resolutIon by pointwise irradiatIon with UV light
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Caged Molecular Glues as Photoactivatable Tags for Nuclear TranslocatIon of Guests in Living Cells
2018Co-Authors: Akio Arisaka, Kou Okuro, Rina Mogaki, Takuzo AidaAbstract:We developed dendritic caged molecular glues (CagedGlue-R) as tags for nucleus-targeted drug delivery, whose multiple Guanidinium Ion (Gu+) pendants are protected by an anIonic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; BANVOC). Negatively charged CagedGlue-R hardly binds to anIonic biomolecules because of their electrostatic repulsIon. However, upon exposure of CagedGlue-R to UV light or near-infrared (NIR) light, the BANVOC groups of CagedGlue-R are rapidly detached to yield an uncaged molecular glue (UncagedGlue-R) that carries multiple Gu+ pendants. Because Gu+ forms a salt bridge with PO4–, UncagedGlue-R tightly adheres to anIonic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formatIon. When tagged with CagedGlue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the CagedGlue-R tag is photochemically uncaged to form UncagedGlue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with CagedGlue-R can be delivered efficiently to cell nuclei eventually by irradiatIon with light
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Guanidinium based molecular glues for modulatIon of biomolecular functIons
Chemical Society Reviews, 2017Co-Authors: Rina Mogaki, Kou Okuro, P K Hashim, Takuzo AidaAbstract:Molecular adhesIon based on multivalent interactIons plays essential roles in various biological processes. Hence, “molecular glues” that can adhere to biomolecules may modulate biomolecular functIons and therefore can be applied to therapeutics. This tutorial review describes design strategies for developing adhesive motifs for biomolecules based on multivalent interactIons. We highlight a Guanidinium Ion-based salt-bridge as a key interactIon for adhesIon to biomolecules and discuss the applicatIon of molecular glues for manipulatIon of biomolecular assemblies, drug delivery systems, and modulatIon of biomolecular functIons.
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molecular glues for manipulating enzymes trypsin inhibitIon by benzamidine conjugated molecular glues
Chemical Science, 2015Co-Authors: Rina Mogaki, Kou Okuro, Takuzo AidaAbstract:Water-soluble bioadhesive polymers bearing multiple Guanidinium Ion (Gu+) pendants at their side-chain termini (Gluen–BA, n = 10 and 29) that were conjugated with benzamidine (BA) as a trypsin inhibitor were developed. The Gluen–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, mGlue27–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.
