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Nucleotide

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Dane A. Sethre-hofstad – One of the best experts on this subject based on the ideXlab platform.

  • Nucleotide P2Y_1 receptor agonists are in vitro and in vivo prodrugs of A_1/A_3 adenosine receptor agonists: implications for roles of P2Y_1 and A_1/A_3 receptors in physiology and pathology
    Purinergic Signalling, 2020
    Co-Authors: Theodore E. Liston, Sonja Hinz, Christa E. Müller, Deborah M. Holstein, Jay Wendling, Roger J. Melton, Mary Campbell, William S. Korinek, R. Rama Suresh, Dane A. Sethre-hofstad
    Abstract:

    Rapid phosphoester hydrolysis of endogenous purine and pyrimidine Nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical Nucleotide P2Y_1 receptor (P2Y_1R) agonists and antagonists. These included the riboside Nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained ( N )-methanocarba rings, which were previously reported to form Nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for Nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A_3 and A_1ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y_1R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to Nucleotide agonists is due to AR activation by active nucleoside metabolites.

Chi-huey Wong – One of the best experts on this subject based on the ideXlab platform.

  • Large-Scale Enzymatic Synthesis of Glycans with Cofactor Regeneration
    Glycoscience: Biology and Medicine, 2021
    Co-Authors: Tsung-i Tsai, Chung-yi Wu, Chi-huey Wong
    Abstract:

    The glycosyltransferases, which catalyze the transfer of a saccharide from a sugar Nucleotide donor to an acceptor, have been used for the synthesis of complex glycoconjugates. Nevertheless, narrow substrate specificity, high cost of both the enzymes and the sugar Nucleotides, and limited enzyme availability limit their application. Moreover, the progression of glycosylation can be plagued by feedback inhibition caused by the generated nucleoside phosphate. Regeneration of the sugar Nucleotide intermediate in situ can reduce the concentration of the nucleoside phosphate by-product by the use of a small amount of the sugar Nucleotide; thus, the expenses of the sugar Nucleotide and product inhibition are reduced simultaneously.

Theodore E. Liston – One of the best experts on this subject based on the ideXlab platform.

  • Nucleotide P2Y_1 receptor agonists are in vitro and in vivo prodrugs of A_1/A_3 adenosine receptor agonists: implications for roles of P2Y_1 and A_1/A_3 receptors in physiology and pathology
    Purinergic Signalling, 2020
    Co-Authors: Theodore E. Liston, Sonja Hinz, Christa E. Müller, Deborah M. Holstein, Jay Wendling, Roger J. Melton, Mary Campbell, William S. Korinek, R. Rama Suresh, Dane A. Sethre-hofstad
    Abstract:

    Rapid phosphoester hydrolysis of endogenous purine and pyrimidine Nucleotides has challenged the characterization of the role of P2 receptors in physiology and pathology. Nucleotide phosphoester stabilization has been pursued on a number of medicinal chemistry fronts. We investigated the in vitro and in vivo stability and pharmacokinetics of prototypical Nucleotide P2Y_1 receptor (P2Y_1R) agonists and antagonists. These included the riboside Nucleotide agonist 2-methylthio-ADP and antagonist MRS2179, as well as agonist MRS2365 and antagonist MRS2500 containing constrained ( N )-methanocarba rings, which were previously reported to form Nucleotides that are more slowly hydrolyzed at the α-phosphoester compared with the ribosides. In vitro incubations in mouse and human plasma and blood demonstrated the rapid hydrolysis of these compounds to nucleoside metabolites. This metabolism was inhibited by EDTA to chelate divalent cations required by ectonucleotidases for Nucleotide hydrolysis. This rapid hydrolysis was confirmed in vivo in mouse pharmacokinetic studies that demonstrate that MRS2365 is a prodrug of the nucleoside metabolite AST-004 (MRS4322). Furthermore, we demonstrate that the nucleoside metabolites of MRS2365 and 2-methylthio-ADP are adenosine receptor (AR) agonists, notably at A_3 and A_1ARs. In vivo efficacy of MRS2365 in murine models of traumatic brain injury and stroke can be attributed to AR activation by its nucleoside metabolite AST-004, rather than P2Y_1R activation. This research suggests the importance of reevaluation of previous in vitro and in vivo research of P2YRs and P2XRs as there is a potential that the pharmacology attributed to Nucleotide agonists is due to AR activation by active nucleoside metabolites.