Ribavirin, tiazofurin, and selenazofurin: mononucleotides and nicotinamide adenine dinucleotide analogs. Synthesis, structure, and interactions with IMP dehydrogenase

Gebeyehu, Gulilat; Márquez, Víctor E.; Cott, A. Van; Cooney, David A.; Kelley, James A.; Jayaram, Hiremagalur N.; Ahluwalia, Gurpreet S.; Dion, Robert L.; Wilson, Yvonne A.; Johns, David G.

doi:10.1021/jm00379a018

Cited by 94 publications

(47 citation statements)

References 4 publications

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“…The dinucleotide inhibitor SAD was introduced by adding Ϸ40 g solid inhibitor to the 4-l droplet containing the crystals. SAD was obtained from K. Pankiewicz and K. Watanabe, prepared according to the methods of Marquez (45).…”

Section: Methodsmentioning

confidence: 99%

“…Thus, we have undertaken the structure determination of a ternary complex of human type II IMPDH. This complex contains the halogenated substrate analogue 6-Cl IMP and the NAD analogue selenazole-4-carboxamide adenine dinucleotide (SAD), the active selenium analogue of the tiazofurin metabolite TAD (45,46). We identify unique structural features relevant to IMPDH-cofactor binding, as well as potentially exploitable differences between the type I and type II isoforms.…”

mentioning

confidence: 99%

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Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Colby

Vanderveen

Strickler

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

138

127

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Inosine monophosphate dehydrogenase (IM-PDH) controls a key metabolic step in the regulation of cell growth and differentiation. This step is the NAD-dependent oxidation of inosine 5 monophosphate (IMP) to xanthosine 5 monophosphate, the rate-limiting step in the synthesis of the guanine nucleotides. Two isoforms of IMPDH have been identified, one of which (type II) is significantly up-regulated in neoplastic and differentiating cells. As such, it has been identified as a major target in antitumor and immunosuppressive drug design. We present here the 2.9-Å structure of a ternary complex of the human type II isoform of IMPDH. The complex contains the substrate analogue 6-chloropurine riboside 5-monophosphate (6-Cl-IMP) and the NAD analogue selenazole-4-carboxamide adenine dinucleotide, the selenium derivative of the active metabolite of the antitumor drug tiazofurin. The enzyme forms a homotetramer, with the dinucleotide binding at the monomer-monomer interface. The 6 chloro-substituted purine base is dehalogenated, forming a covalent adduct at C6 with Cys-331. The dinucleotide selenazole base is stacked against the 6-Cl-IMP purine ring in an orientation consistent with the B-side stereochemistry of hydride transfer seen with NAD. The adenosine end of the ligand interacts with residues not conserved between the type I and type II isoforms, suggesting strategies for the design of isoform-specific agents.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Colby

Vanderveen

Strickler

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

138

127

View full text Add to dashboard Cite

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“…Other compounds that only inhibit nucleotide pools have not been effective antiviral agents in vivo, such as mycophenolic acid (14); tiazofurin (6,12); selenazofurin (6,12); and, most relevant to this study, 6-azauridine (23). It is our hypothesis that if the primary mode of antiviral action of an agent is via nucleotide pool depletion, that compound will not be a very effective drug in vivo.…”

Section: Pyrimidine Nucleosides (3)mentioning

confidence: 99%

Novel pyrazolo[3,4-d]pyrimidine nucleoside analog with broad-spectrum antiviral activity

Smee¹,

McKernan²,

Nord³

et al. 1987

Antimicrob Agents Chemother

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A novel nucleoside analog, 4(5H)-oxo-l1-,-D-ribofuranosylpyrazolo [3,4-d]pyrimidine-3-thiocarboxamide (N10169), was evaluated in cell culture and in animals for antiviral activity against DNA and RNA viruses. The compound was highly active against strains of adeno-, vaccinia, influenza B, paramyxo-, picorna-, and reoviruses, with 50% inhibition of virus-induced cytopathology at 1 to 10 ,uM. Lesser or no antiviral effects were observed against herpes simplex, cytomegalo-, corona-, influenza A, vesicular stomatitis, and visna viruses. Drug potency against certain viruses was highly cell line dependent (N10169 was highly active in HeLa cells but was much less potent in Vero cells). This was correlated, in part, to differences in levels of adenosine kinase activity in these cell lines, since adenosine kinase appears to phosphorylate N10169 to its active form.N10169 was inhibitory to proliferating cells at antiviral concentrations, whereas stationary-phase monolayers tolerated higher concentrations (5100 ,uM). Exogenous uridine was able to reverse the virus-inhibitory effects of the compound, leading to the discovery that N10169 5'-monophosphate is a potent inhibitor of cellular orotidylate decarboxylase. N10169 was evaluated in mice that were infected intraperitoneally with banzi virus or inoculated intranasally with influenza B virus, and in hamsters that were infected intranasally with vaccinia virus. In each model, intraperitoneal injection of N10169 (100 to 300 mg/kg per day for 7 days) twice daily was ineffective, whereas intraperitoneal injection of ribavirin showed some benefit in the influenza B and banzi virus infection models.In a recent report (3) a series of pyrazolo [3,4-d]pyrimidine nucleoside analogs possessing antiviral and antitumor properties was described. Additional studies of these compounds were undertaken to determine the spectrum of viruses which would be inhibited and to ascertain any therapeutic potential in animals. One compound, 4(5H)-oxo-1-P-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3-thiocarboxamide (N10169; Fig. 1), although similar in structure to the broad-spectrum antiviral agent ribavirin (18), was found to have an unusual spectrum of antiviral activity, degree of potency, and mode of action. Although the compound is related to purine nucleosides, it was found to be a potent inhibitor of pyrimidine biosynthesis. As the work proceeded it was determined that the properties of N10169 were remarkably similar to those of 6-azauridine (23). The compounds related to N10169 (3) did not exhibit the same degree of potency and spectrum of activity that N10169 did in vitro. In this report we summarize the results of cell culture studies and evaluate the antiviral activity of this novel compound in appropriate animal infection models.

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“…Recently, it was demonstrated that selenazofurin also reduces the concentration of guanosine nucleotides in treated cells (12). The reduction of the GTP pool by these two agents is thought to be due to the inhibition of IMP dehydrogenase, an enzyme in the GTP biosynthetic pathway (4,11,16). Metabolites of the two drugs inhibited purifed IMP dehydrogenase isolated from either P388 or Ehrlich ascites cells (6,16).…”

mentioning

confidence: 99%

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses

Wray¹,

Smith²,

Gilbert³

et al. 1986

Antimicrob Agents Chemother

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We studied the effects of selenazofurin alone and in combination with ribavirin on replication of influenza A and B viruses. These drugs showed little cytotoxicity as measured by leucine incorporation into protein in MDCK cells, although they were potent inhibitors of viral replication in the same cells. Selenazofurin inhibited growth of influenza A and B viruses at concentrations (50% inhibitory dose = 25 and 19 ,uM, respectively) which were similar to those at which growth was inhibited by ribavirin (50% inhibitory dose = 50 and 30 ,uM, respectively). The inhibition of replication of either influenza A or B virus was additive for any combination of ribavirin and selenazofurin. The effects of the 5'-triphosphate of selenazofurin on two replicative functions associated with the influenza virus RNA-dependent RNA polymerases, primer generation (initiation of transcription) and its subsequent elongation, were measured. Elongation was more sensitive to selenazofurin 5'-triphosphate than was primer generation, and the effects of this drug on these functions were approximately the same as those of ribavirin 5'-triphosphate. The activities of ribavirin triphosphate and selenazofurin triphosphate were additive, and combinations did not potentiate the individual inhibitory effects of these drugs on elongation.Selenazofurin (2-p-D-ribofuranosylselenazole-4-carboxamide)is a new synthetic nucleoside analog which is structurally related to ribavirin, a potent broad-spectrum antiviral agent (15). Selenazofurin is a potent antiviral agent in vitro, inhibiting the replication of such diverse viruses as

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Ribavirin, tiazofurin, and selenazofurin: mononucleotides and nicotinamide adenine dinucleotide analogs. Synthesis, structure, and interactions with IMP dehydrogenase

Cited by 94 publications

References 4 publications

Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Crystal structure of human type II inosine monophosphate dehydrogenase: Implications for ligand binding and drug design

Novel pyrazolo[3,4-d]pyrimidine nucleoside analog with broad-spectrum antiviral activity

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses

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