The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Francesc X Aviles - One of the best experts on this subject based on the ideXlab platform.
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synthesis And structurAl functionAl chArActerizAtion of selective m14 metAlloCArboxypeptidAse inhibitors bAsed on phosphinic pseudopeptide scAffold implicAtions on the design of specific opticAl probes
Journal of Medicinal Chemistry, 2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the ...
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Synthesis And StructurAl/FunctionAl ChArActerizAtion of Selective M14 MetAlloCArboxypeptidAse Inhibitors BAsed on Phosphinic Pseudopeptide ScAffold: ImplicAtions on the Design of Specific OpticAl Probes
2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the first exAmple of chemicAl probes useful to selectively report on type-A MCPs Activity in complex mediA
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crystAl structure of AviAn CArboxypeptidAse d domAin ii A prototype for the regulAtory metAlloCArboxypeptidAse subfAmily
The EMBO Journal, 1999Co-Authors: F X Gomisruth, Josep Vendrell, Francesc X Aviles, V Companys, Y Qian, Lloyd D Fricker, Miquel CollAbstract:The crystAl structure of domAin II of duck CArboxypeptidAse D, A prohormone/propeptide processing enzyme integrAted in A three repeAt tAndem in the nAturAl system, hAs been solved, constituting A prototype for members of the regulAtory metAlloCArboxypeptidAse subfAmily. It displAys A 300 residue N‐terminAl α/β‐hydrolAse subdomAin with overAll topologicAl similArity to And generAl coincidence of the key cAtAlytic residues with the ArchetypAl pAncreAtic CArboxypeptidAse A. However, numerous significAnt insertions/deletions in segments forming the funnel‐like Access to the Active site explAin differences in specificity towArds lArger protein substrAtes or inhibitors. This α/β‐hydrolAse subdomAin is followed by A C‐terminAl 80 residue β‐sAndwich subdomAin, unique for these regulAtory metAlloenzymes And topologicAlly relAted to trAnsthyretin And sugAr‐binding proteins. The structure described here estAblishes the fundAmentAls for A better understAnding of the mechAnism ruling events such As prohormone processing And will enAble modelling of regulAtory CArboxypeptidAses As well As A more rAtionAl design of inhibitors of CArboxypeptidAse D.
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differentiAl scAnning cAlorimetric study of CArboxypeptidAse b proCArboxypeptidAse b And its globulAr ActivAtion domAin
FEBS Journal, 1991Co-Authors: Francisco Conejerolara, Josep Vendrell, Pedro L. Mateo, Jose M Sanchezruiz, Francisco J Burgos, Francesc X AvilesAbstract:High-sensitivity differentiAl scAnning cAlorimetry hAs been Applied to the study of porcine pAncreAtic CArboxypeptidAse B, the proenzyme And its 81-residue ActivAtion domAin. The thermAl study hAs been cArried out over A rAnge of scAn rAtes, ionic strengths And pH vAlues. The thermAl unfolding of the isolAted ActivAtion domAin hAs been found to be reversible And corresponds to thAt of A typicAl compAct globulAr structure, with melting temperAtures higher thAn those of the enzyme And proenzyme. Both proteins, on the other hAnd, undergo An irreversible, highly scAn-rAte-dependent thermAl denAturAtion under All the experimentAl conditions investigAted. The denAturAtion of the enzyme At pH 7.5 And the proenzyme At pH 7.5 And 9.0 follows the two-stAte irreversible model [SAnchez-Ruiz, J.M., Lopez-LAcombA, J.L., Cortijo, M. & MAteo, P.L. (1988) Biochemistry 27, 1648-1652]. Thus the kinetic constAnts And ActivAtion pArAmeters of the denAturAtion process could be obtAined And compAred to those for other proteins, pArticulArly those of the closely relAted CArboxypeptidAse A system.
Josep Vendrell - One of the best experts on this subject based on the ideXlab platform.
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synthesis And structurAl functionAl chArActerizAtion of selective m14 metAlloCArboxypeptidAse inhibitors bAsed on phosphinic pseudopeptide scAffold implicAtions on the design of specific opticAl probes
Journal of Medicinal Chemistry, 2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the ...
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Synthesis And StructurAl/FunctionAl ChArActerizAtion of Selective M14 MetAlloCArboxypeptidAse Inhibitors BAsed on Phosphinic Pseudopeptide ScAffold: ImplicAtions on the Design of Specific OpticAl Probes
2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the first exAmple of chemicAl probes useful to selectively report on type-A MCPs Activity in complex mediA
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Discovery of MechAnism-BAsed InActivAtors for HumAn PAncreAtic CArboxypeptidAse A from A Focused Synthetic LibrAry
2017Co-Authors: Sebastián A. Testero, Josep Vendrell, Giovanni Covaleda, Pablo Gallego, David Reverter, Carla Granados, Daniel Fernández, Francesc X. Avilés, Irantzu Pallarès, Shahriar MobasheryAbstract:MetAlloCArboxypeptidAses (MCPs) Are involved in mAny biologicAl processes such As fibrinolysis or inflAmmAtion, development, Alzheimer’s diseAse, And vArious types of cAncer. We describe the synthesis And kinetic chArActerizAtion of A focused librAry of 22 thiirAne- And oxirAne-bAsed potentiAl mechAnism-bAsed inhibitors, which led to discovery of An inhibitor for the humAn pro-CArboxypeptidAse A1. Our structurAl AnAlyses show thAt the thiirAne-bAsed smAll-molecule inhibitor penetrAtes the bArrier of the pro-domAin to bind within the Active site. This binding leAds to A chemicAl reAction thAt covAlently modifies the cAtAlytic Glu270. These results highlight the importAnce of combined structurAl, biophysicAl, And biochemicAl evAluAtion of inhibitors in design strAtegies for the development of spectroscopicAlly nonsilent probes As effective beAcons for in vitro, in cellulo, And/or in vivo locAlizAtion in clinicAl And industriAl ApplicAtions
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crystAl structure of AviAn CArboxypeptidAse d domAin ii A prototype for the regulAtory metAlloCArboxypeptidAse subfAmily
The EMBO Journal, 1999Co-Authors: F X Gomisruth, Josep Vendrell, Francesc X Aviles, V Companys, Y Qian, Lloyd D Fricker, Miquel CollAbstract:The crystAl structure of domAin II of duck CArboxypeptidAse D, A prohormone/propeptide processing enzyme integrAted in A three repeAt tAndem in the nAturAl system, hAs been solved, constituting A prototype for members of the regulAtory metAlloCArboxypeptidAse subfAmily. It displAys A 300 residue N‐terminAl α/β‐hydrolAse subdomAin with overAll topologicAl similArity to And generAl coincidence of the key cAtAlytic residues with the ArchetypAl pAncreAtic CArboxypeptidAse A. However, numerous significAnt insertions/deletions in segments forming the funnel‐like Access to the Active site explAin differences in specificity towArds lArger protein substrAtes or inhibitors. This α/β‐hydrolAse subdomAin is followed by A C‐terminAl 80 residue β‐sAndwich subdomAin, unique for these regulAtory metAlloenzymes And topologicAlly relAted to trAnsthyretin And sugAr‐binding proteins. The structure described here estAblishes the fundAmentAls for A better understAnding of the mechAnism ruling events such As prohormone processing And will enAble modelling of regulAtory CArboxypeptidAses As well As A more rAtionAl design of inhibitors of CArboxypeptidAse D.
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differentiAl scAnning cAlorimetric study of CArboxypeptidAse b proCArboxypeptidAse b And its globulAr ActivAtion domAin
FEBS Journal, 1991Co-Authors: Francisco Conejerolara, Josep Vendrell, Pedro L. Mateo, Jose M Sanchezruiz, Francisco J Burgos, Francesc X AvilesAbstract:High-sensitivity differentiAl scAnning cAlorimetry hAs been Applied to the study of porcine pAncreAtic CArboxypeptidAse B, the proenzyme And its 81-residue ActivAtion domAin. The thermAl study hAs been cArried out over A rAnge of scAn rAtes, ionic strengths And pH vAlues. The thermAl unfolding of the isolAted ActivAtion domAin hAs been found to be reversible And corresponds to thAt of A typicAl compAct globulAr structure, with melting temperAtures higher thAn those of the enzyme And proenzyme. Both proteins, on the other hAnd, undergo An irreversible, highly scAn-rAte-dependent thermAl denAturAtion under All the experimentAl conditions investigAted. The denAturAtion of the enzyme At pH 7.5 And the proenzyme At pH 7.5 And 9.0 follows the two-stAte irreversible model [SAnchez-Ruiz, J.M., Lopez-LAcombA, J.L., Cortijo, M. & MAteo, P.L. (1988) Biochemistry 27, 1648-1652]. Thus the kinetic constAnts And ActivAtion pArAmeters of the denAturAtion process could be obtAined And compAred to those for other proteins, pArticulArly those of the closely relAted CArboxypeptidAse A system.
L. Devel - One of the best experts on this subject based on the ideXlab platform.
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synthesis And structurAl functionAl chArActerizAtion of selective m14 metAlloCArboxypeptidAse inhibitors bAsed on phosphinic pseudopeptide scAffold implicAtions on the design of specific opticAl probes
Journal of Medicinal Chemistry, 2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the ...
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Synthesis And StructurAl/FunctionAl ChArActerizAtion of Selective M14 MetAlloCArboxypeptidAse Inhibitors BAsed on Phosphinic Pseudopeptide ScAffold: ImplicAtions on the Design of Specific OpticAl Probes
2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the first exAmple of chemicAl probes useful to selectively report on type-A MCPs Activity in complex mediA
Giovanni Covaleda - One of the best experts on this subject based on the ideXlab platform.
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synthesis And structurAl functionAl chArActerizAtion of selective m14 metAlloCArboxypeptidAse inhibitors bAsed on phosphinic pseudopeptide scAffold implicAtions on the design of specific opticAl probes
Journal of Medicinal Chemistry, 2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the ...
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Synthesis And StructurAl/FunctionAl ChArActerizAtion of Selective M14 MetAlloCArboxypeptidAse Inhibitors BAsed on Phosphinic Pseudopeptide ScAffold: ImplicAtions on the Design of Specific OpticAl Probes
2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the first exAmple of chemicAl probes useful to selectively report on type-A MCPs Activity in complex mediA
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Discovery of MechAnism-BAsed InActivAtors for HumAn PAncreAtic CArboxypeptidAse A from A Focused Synthetic LibrAry
2017Co-Authors: Sebastián A. Testero, Josep Vendrell, Giovanni Covaleda, Pablo Gallego, David Reverter, Carla Granados, Daniel Fernández, Francesc X. Avilés, Irantzu Pallarès, Shahriar MobasheryAbstract:MetAlloCArboxypeptidAses (MCPs) Are involved in mAny biologicAl processes such As fibrinolysis or inflAmmAtion, development, Alzheimer’s diseAse, And vArious types of cAncer. We describe the synthesis And kinetic chArActerizAtion of A focused librAry of 22 thiirAne- And oxirAne-bAsed potentiAl mechAnism-bAsed inhibitors, which led to discovery of An inhibitor for the humAn pro-CArboxypeptidAse A1. Our structurAl AnAlyses show thAt the thiirAne-bAsed smAll-molecule inhibitor penetrAtes the bArrier of the pro-domAin to bind within the Active site. This binding leAds to A chemicAl reAction thAt covAlently modifies the cAtAlytic Glu270. These results highlight the importAnce of combined structurAl, biophysicAl, And biochemicAl evAluAtion of inhibitors in design strAtegies for the development of spectroscopicAlly nonsilent probes As effective beAcons for in vitro, in cellulo, And/or in vivo locAlizAtion in clinicAl And industriAl ApplicAtions
Pablo Gallego - One of the best experts on this subject based on the ideXlab platform.
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synthesis And structurAl functionAl chArActerizAtion of selective m14 metAlloCArboxypeptidAse inhibitors bAsed on phosphinic pseudopeptide scAffold implicAtions on the design of specific opticAl probes
Journal of Medicinal Chemistry, 2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the ...
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Synthesis And StructurAl/FunctionAl ChArActerizAtion of Selective M14 MetAlloCArboxypeptidAse Inhibitors BAsed on Phosphinic Pseudopeptide ScAffold: ImplicAtions on the Design of Specific OpticAl Probes
2019Co-Authors: Giovanni Covaleda, Josep Vendrell, Francesc X Aviles, Pablo Gallego, Dimitris Georgiadis, Julia Lorenzo, Vincent Dive, David Reverter, L. DevelAbstract:MetAlloCArboxypeptidAses (MCPs) of the M14 fAmily Are Zn2+-dependent exoproteAses present in Almost every tissue or fluid in mAmmAls. These enzymes perform A lArge vAriety of physiologicAl functions And Are involved in severAl pAthologies, such As pAncreAtic diseAses, inflAmmAtion, fibrinolysis, And cAncer. Here, we describe the synthesis And functionAl/structurAl chArActerizAtion of A series of reversible tight-binding phosphinic pseudopeptide inhibitors thAt show high specificity And potency towArd these proteAses. ChArActerizAtion of their inhibitory potentiAl AgAinst A lArge vAriety of MCPs, combined with high-resolution crystAl structures of three selected cAndidAtes in complex with humAn CArboxypeptidAse A (CPA)1, Allowed to decipher the structurAl determinAnts governing selectivity for type-A of the M14A MCP fAmily. Further, the phosphinic pseudopeptide frAmework wAs exploited to generAte An opticAl probe selectively tArgeting humAn CPAs. The phosphinic pseudopeptides presented here constitute the first exAmple of chemicAl probes useful to selectively report on type-A MCPs Activity in complex mediA
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Discovery of MechAnism-BAsed InActivAtors for HumAn PAncreAtic CArboxypeptidAse A from A Focused Synthetic LibrAry
2017Co-Authors: Sebastián A. Testero, Josep Vendrell, Giovanni Covaleda, Pablo Gallego, David Reverter, Carla Granados, Daniel Fernández, Francesc X. Avilés, Irantzu Pallarès, Shahriar MobasheryAbstract:MetAlloCArboxypeptidAses (MCPs) Are involved in mAny biologicAl processes such As fibrinolysis or inflAmmAtion, development, Alzheimer’s diseAse, And vArious types of cAncer. We describe the synthesis And kinetic chArActerizAtion of A focused librAry of 22 thiirAne- And oxirAne-bAsed potentiAl mechAnism-bAsed inhibitors, which led to discovery of An inhibitor for the humAn pro-CArboxypeptidAse A1. Our structurAl AnAlyses show thAt the thiirAne-bAsed smAll-molecule inhibitor penetrAtes the bArrier of the pro-domAin to bind within the Active site. This binding leAds to A chemicAl reAction thAt covAlently modifies the cAtAlytic Glu270. These results highlight the importAnce of combined structurAl, biophysicAl, And biochemicAl evAluAtion of inhibitors in design strAtegies for the development of spectroscopicAlly nonsilent probes As effective beAcons for in vitro, in cellulo, And/or in vivo locAlizAtion in clinicAl And industriAl ApplicAtions