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Claudiu T Supuran – One of the best experts on this subject based on the ideXlab platform.

  • Carbonic anhydrase Activators: activation of human isozymes I, II and IX with phenylsulfonylhydrazido l-histidine derivatives.
    Bioorganic & Medicinal Chemistry Letters, 2009
    Co-Authors: Marie-rose Abdo, Andrea Scozzafava, Daniela Vullo, Mohamed-chiheb Saada, Jean-louis Montero, Jean-yves Winum, Claudiu T Supuran

    Abstract:

    Abstract Activation of the human carbonic anhydrase (CA, EC 4.2.1.1) isozymes I, II (cytosolic) and IX (transmembrane, tumor-associated isoform) with a series of arylsulfonylhydrazido- l -histidines incorporating 4-substituted-phenyl, pentafluorophenyl- and β-naphthyl moieties was investigated. The compounds showed a weak hCA I activation profile, but were more efficient as hCA II and IX Activators. The 4-iodophenyl-substituted derivative behaved as a strong and isozyme selective hCA II Activator, with an activation constant of 0.21 μM. This is the first isoform-selective, potent CA Activator reported to date.

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  • carbonic anhydrase Activators activation of isozymes i ii iv va vii and xiv with l and d histidine and crystallographic analysis of their adducts with isoform ii engineering proton transfer processes within the active site of an enzyme
    Chemistry: A European Journal, 2006
    Co-Authors: Claudia Temperini, Andrea Scozzafava, Daniela Vullo, Claudiu T Supuran

    Abstract:

    Activation of six human carbonic anhydrases (CA, EC 4.2.1.1), that is, hCA I, II, IV, VA, VII, and XIV, with L- and D-histidine was investigated through kinetics and by X-ray crystallography. L-His was a potent Activator of isozymes I, VA, VII, and XIV, and a weaker Activator of hCA II and IV. D-His showed good hCA I, VA, and VII activation properties, being a moderate Activator of hCA XIV and a weak Activator of hCA II and IV. The structures as determined by X-ray crystallography of the hCA II-L-His/D-His adducts showed the Activators to be anchored at the entrance of the active site, contributing to extended networks of hydrogen bonds with amino acid residues/water molecules present in the cavity, explaining their different potency and interaction patterns with various isozymes. The residues involved in L-His recognition were His64, Asn67, Gln92, whereas three water molecules connected the Activator to the zinc-bound hydroxide. Only the imidazole moiety of L-His interacted with these amino acids. For the D-His adduct, the residues involved in recognition of the Activator were Trp5, His64, and Pro201, whereas two water molecules connected the zinc-bound water to the Activator. Only the COOH and NH 2 moieties of D-His participated in hydrogen bonds with these residues. This is the first study showing different binding modes of stereoisomeric Activators within the hCA II active site, with consequences for overall proton-transfer processes (rate-determining for the catalytic cycle). The study also points out differences of activation efficiency between various isozymes with structurally related Activators, convenient for designing alternative proton-transfer pathways, useful both for a better understanding of the catalytic mechanism and for obtaining pharmacologically useful derivatives, for example, for the management of Alzheimer’s disease.

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  • carbonic anhydrase Activators activation of isoforms i ii iv va vii and xiv with l and d phenylalanine and crystallographic analysis of their adducts with isozyme ii stereospecific recognition within the active site of an enzyme and its consequences
    Journal of Medicinal Chemistry, 2006
    Co-Authors: Claudia Temperini, Andrea Scozzafava, Daniela Vullo, Claudiu T Supuran

    Abstract:

    Activation of six human brain carbonic anhydrases (hCAs, EC 4.2.1.1), hCA I, II, IV, VA, VII, and XIV, with l-/d-phenylalanine was investigated kinetically and by X-ray crystallography. l-Phe was a potent Activator of isozymes I, II, and XIV (KAs of 13−240 nM), a weaker Activator of hCA VA and VII (KAs of 9.8−10.9 μM), and a quite inefficient hCA IV Activator (KA of 52 μM). d-Phe showed good hCA II Activatory properties (KA of 35 nM), being a moderate hCA VA, VII, and XIV (KAs of 4.6−9.7 μM) and a weak hCA I and IV Activator (KAs of 63−86 μM). X-ray crystallography of the hCA II−l-Phe/d-Phe adducts showed the Activators to be anchored at the entrance of the active site, participating in numerous bonds and hydrophobic interactions with amino acid residues His64, Thr200, Trp5, and Pro201. This is the first study showing different binding modes of stereoisomeric Activators within the hCA II active site, with consequences for overall proton transfer processes (rate-determining for the catalytic cycle). It als…

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Henri R. Lijnen – One of the best experts on this subject based on the ideXlab platform.

  • Novel thrombolytic agents
    Cardiovascular Drugs and Therapy, 1994
    Co-Authors: Marc Verstraete, Henri R. Lijnen

    Abstract:

    The fibrinolytic system comprises an inactive proenzyme, plasminogen, that is converted by plasminogen Activators to the active enzyme, plasmin, that degrades fibrin. Two immunologically distinct plasminogen Activators have been identified: tissue-type plasminogen Activator (t-PA) and urokinase-type plasminogen Activator (u-PA). Plasminogen activation is regulated by specific molecular interactions between its main components, as well as by controlled synthesis and release of plasminogen Activator inhibitors, primarily from endothelial cells. The observed association between abnormal fibrinolysis and a tendency toward bleeding or thrombosis demonstrates the (patho)physiological importance of the fibrinolytic system. Transgenic animals are a suitable experimental model to examine the in vivo impact of fibrinolytic components in thrombosis and thrombolysis. Inactivation, by homologous recombination, of the tissue-type plasminogen Activator genes in mice impairs thrombolysis in a significant manner whereas inactivation of the plasminogen Activator-1 gene enhances the rate of spontaneous lysis. Despite their widespread use all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion and bleeding complications. Therefore, the quest for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrinselectivity continues. Several lines of research toward improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen Activators, chimeric plasminogen Activators, conjugates of plasminogen Activators with monoclonal antibodies, or plasminogen Activators from animal or bacterial origin.

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Marc Verstraete – One of the best experts on this subject based on the ideXlab platform.

  • Novel thrombolytic agents
    Cardiovascular Drugs and Therapy, 1994
    Co-Authors: Marc Verstraete, Henri R. Lijnen

    Abstract:

    The fibrinolytic system comprises an inactive proenzyme, plasminogen, that is converted by plasminogen Activators to the active enzyme, plasmin, that degrades fibrin. Two immunologically distinct plasminogen Activators have been identified: tissue-type plasminogen Activator (t-PA) and urokinase-type plasminogen Activator (u-PA). Plasminogen activation is regulated by specific molecular interactions between its main components, as well as by controlled synthesis and release of plasminogen Activator inhibitors, primarily from endothelial cells. The observed association between abnormal fibrinolysis and a tendency toward bleeding or thrombosis demonstrates the (patho)physiological importance of the fibrinolytic system. Transgenic animals are a suitable experimental model to examine the in vivo impact of fibrinolytic components in thrombosis and thrombolysis. Inactivation, by homologous recombination, of the tissue-type plasminogen Activator genes in mice impairs thrombolysis in a significant manner whereas inactivation of the plasminogen Activator-1 gene enhances the rate of spontaneous lysis. Despite their widespread use all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion and bleeding complications. Therefore, the quest for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrinselectivity continues. Several lines of research toward improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen Activators, chimeric plasminogen Activators, conjugates of plasminogen Activators with monoclonal antibodies, or plasminogen Activators from animal or bacterial origin.

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