Inosine monophosphate dehydrogenase as a target for antiviral, anticancer, antimicrobial and immunosuppressive therapeutics

Future Medicinal Chemistry

Volumn 2, Issue 1, 2010, Pages 81-92

  Braun Sand, Sonja B ^a   Peetz, Matthew ^a  

^a UNIVERSITY OF COLORADO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AVN 944; HYDROXAMIC ACID; IMATINIB; INOSINATE DEHYDROGENASE; INOSINATE DEHYDROGENASE 1; INOSINATE DEHYDROGENASE 2; INOSINATE DEHYDROGENASE INHIBITOR; ISOENZYME; MERIMEPODIB; MYCOPHENOLIC ACID; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; MYCOPHENOLIC HYDROXAMIC ACID; PEGINTERFERON ALPHA; PEGINTERFERON ALPHA2B; RIBAVIRIN; TARIBAVIRIN; TIAZOFURIN; UNCLASSIFIED DRUG; VX 944;

ANEMIA; BIRTH DEFECT; CANCER INHIBITION; CANCER THERAPY; CATALYSIS; CHRONIC MYELOID LEUKEMIA; CLINICAL TRIAL; DENGUE; DEPRESSION; DNA VIRUS; DRUG EFFECT; DRUG TARGETING; ENZYME MECHANISM; FATIGUE; GENE EXPRESSION; GRAFT REJECTION; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; NEOPLASM; NONHUMAN; PREVALENCE; PRIORITY JOURNAL; REVIEW; RNA VIRUS; VIRUS INFECTION; VIRUS LOAD; VIRUS REPLICATION;

EID: 77953426717     PISSN: 17568919     EISSN: None     Source Type: Journal    
DOI: 10.4155/fmc.09.147     Document Type: Review

References (98)

1. Hedstrom L. IMP Dehydrogenase: structure, mechanism, and inhibition. Chem. Rev. 109(7), 2903-2928 (2009).
2. Pankiewicz KW, Goldstein BM. Inosine monophosphate dehydrogenase: a major therapeutic target. ACS Symp. Ser. 839, 247-282 (2003).
3. Chen L, Pankiewicz KW. Recent development of IMP dehydrogenase inhibitors for the treatment of cancer. Curr. Opin. Drug Discov. Devel. 10(4), 403-412 (2007).
4. Furuta Y, Takahashi K, Shiraki K et al. T-705 (favipiravir) and related compounds: novel broad-spectrum inhibitors of RNA viral infections. Antiviral Res. 82(3), 95-102 (2009).
5. Hedstrom L, Gan L. IMP dehydrogenase: structural schizophrenia and an unusual base. Curr. Opin. Chem. Biol. 10(5), 520-525 (2006).
6. Nair V, Shu Q. Inosine monophosphate dehydrogenase as a probe in antiviral drug discovery. Antiviral Chem. Chemother. 18(5), 245-258 (2007).
7. Olah E, Kokeny S, Papp J, Bozsik A, Keszei M. Modulation of cancer pathways by inhibitors of guanylate metabolism. Adv. Enzyme Regul. 46, 176-190 (2006).
8. Ratcliffe AJ. Inosine 5́-monophosphate dehydrogenase inhibitors for the treatment of autoimmune diseases. Curr. Opin. Drug Discov. Devel. 9(5), 595-605 (2006).
9. Remichkova M. The antiherpes effect of acyclovir is potentiated by the inhibitors of inosine 5́-monophosphate dehydrogenase - ribavirin, mycophenolic acid and mizoribine. Biotechnol. Biotechnol. Equip. 19(1), 23-27 (2005).
10. Gan L, Petsko Gregory A, Hedstrom L. Crystal structure of a ternary complex of Tritrichomonas foetus inosine 5́-monophosphate dehydrogenase: NAD+ orients the active site loop for catalysis. Biochemistry 41(44), 13309-13317 (2002).
11. Gan L, Seyedsayamdost MR, Shuto S, Matsuda A, Petsko GA, Hedstrom L. The immunosuppressive agent mizoribine monophosphate forms a transition state analog complex with inosine monophosphate dehydrogenase. Biochemistry 42(4), 857-863 (2003).
12. Prosise GL, Wu JZ, Luecke H. Crystal structure of tritrichomonas foetus inosine monophosphate dehydrogenase in complex with the inhibitor ribavirin monophosphate reveals a catalysis-dependent ion-binding site. J. Biol. Chem. 277(52), 50654-50659 (2002).
13. Prosise GL, Luecke H. Crystal structures of tritrichomonas foetus inosine monophosphate dehydrogenase in complex with substrate, cofactor and analogs: a structural basis for the random-in ordered-out kinetic mechanism. J. Mol. Biol. 326(2), 517-527 (2003).
14. Whitby FG, Luecke H, Kuhn P et al. Crystal structure of tritrichomonas foetus inosine-5́- monophosphate dehydrogenase and the enzyme-product complex. Biochemistry 36(35), 10666-10674 (1997).
15. Colby TD, Vanderveen K, Strickler MD, Markham GD, Goldstein BM. Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Proc. Natl Acad. Sci. USA 96(7), 3531-3536 (1999).
16. Zhang R-g, Evans G, Rotella FJ et al. Characteristics and crystal structure of bacterial inosine-5́-monophosphate dehydrogenase. Biochemistry 38(15), 4691-4700 (1999).
17. McMillan FM, Cahoon M, White A, Hedstrom L, Petsko GA, Ringe D. Crystal structure at 2.4 A resolution of Borrelia burgdorferi inosine 5́-monophosphate dehydrogenase: evidence of a substrate-induced hinged-lid motion by loop 6. Biochemistry 39(15), 4533-4542 (2000).
18. Sintchak MD, Fleming MA, Futer O et al. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell 85(6), 921-930 (1996).
19. Bowne SJ, Sullivan LS, Blanton SH et al. Mutations in the inosine monophosphate dehydrogenase 1 gene (IMPDH1) cause the RP10 form of autosomal dominant retinitis pigmentosa. Hum. Mol. Genet. 11(5), 559-568 (2002).
20. Scott JW, Hawley SA, Green KA et al. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J. Clin. Invest. 113(2), 274-284 (2004).
21. Janosik M, Kery V, Gaustadnes M, MacLean KN, Kraus JP. Regulation of human cystathionine Î-synthase by S-adenosyl-l-methionine: evidence for two catalytically active conformations involving an autoinhibitory domain in the C-terminal region. Biochemistry 40(35), 10625-10633 (2001).
22. Meyer S, Savaresi S, Forster IC, Dutzler R. Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5. Nat. Struct. Mol. Biol. 14(1), 60-67 (2007).
23. Jaemsen J, Tuominen H, Salminen A et al. A CBS domain-containing pyrophosphatase of Moorella thermoacetica is regulated by adenine nucleotides. Biochem. J. 408(3), 327-333 (2007).
24. Bennetts B, Rychkov GY, Ng H-L et al. Cytoplasmic ATP-sensing domains regulate gating of skeletal muscle ClC-1 chloride channels. J. Biol. Chem. 280(37), 32452-32458 (2005).
25. Carr SF, Papp E, Wu JC, Natsumeda Y. Characterization of human type I and type II IMP dehydrogenases. J. Biol. Chem. 268(36), 27286-27290 (1993).
26. Holmes EW, Pehlke DM, Kelley WN. Human IMP dehydrogenase. Kinetics and regulatory properties. Biochim. Biophys. Acta Enzymol. 364(2), 209-217 (1974).
27. Mortimer SE, Hedstrom L. Autosomal dominant retinitis pigmentosa mutations in inosine 5́-monophosphate dehydrogenase type I disrupt nucleic acid binding. Biochem. J. 390(1), 41-47 (2005).
28. Pimkin M, Markham GD. The CBS subdomain of inosine 5́-monophosphate dehydrogenase regulates purine nucleotide turnover. Mol. Microbiol. 68(2), 342-359 (2008).
29. Natsumeda Y, Ohno S, Kawasaki H, Konno Y, Weber G, Suzuki K. Two distinct cDNAs for human IMP dehydrogenase. J. Biol. Chem. 265(9), 5292-5295 (1990).
30. Shu Q, Nair V. Inosine monophosphate dehydrogenase (IMPDH) as a target in drug discovery. Med. Res. Rev. 28(2), 219-232 (2008).
31. Jain J, Almquist SJ, Ford PJ et al. Regulation of inosine monophosphate dehydrogenase type I and type II isoforms in human lymphocytes. Biochem. Pharmacol. 67(4), 767-776 (2004).
32. Gu JJ, Tolin AK, Jain J, Huang H, Santiago L, Mitchell BS. Targeted disruption of the inosine 5́-monophosphate dehydrogenase type I gene in mice. Mol. Cell. Biol. 23(18), 6702-6712 (2003).
33. Senda M, Natsumeda Y. Tissue-differential expression of two distinct genes for human IMP dehydrogenase (E.C.1.1.1.205). Life Sci. 54(24), 1917-1926 (1994).
34. Bremer S, Vethe Nils T, Rootwelt H, Bergan S. Expression of IMPDH1 is regulated in response to mycophenolate concentration. Int. Immunopharmacol. 9(2), 173-180 (2009).
35. Gish RG. Treating HCV with ribavirin analogues and ribavirin-like molecules. J. Antimicrob. Chemother. 57(1), 8-13 (2006).
36. Dayton JS, Lindsten T, Thompson CB, Mitchell BS. Effects of human T lymphocyte activation on inosine monophosphate dehydrogenase expression. J. Immunol. 152(3), 984-991 (1994).
37. Digits JA, Hedstrom L. Kinetic mechanism of tritrichomonas foetus inosine 5́-monophosphate dehydrogenase. Biochemistry 38(8), 2295-2306 (1999).
38. Wang W, Hedstrom L. Kinetic mechanism of human inosine 5́-monophosphate dehydrogenase type II: random addition of substrates and ordered release of products. Biochemistry 36(28), 8479-8483 (1997).
39. Riera TV, Wang W, Josephine HR, Hedstrom L. A kinetic alignment of orthologous inosine-5́-monophosphate dehydrogenases. Biochemistry 47(33), 8689-8696 (2008).
40. Xiang B, Markham GD. Probing the mechanism of inosine monophosphate dehydrogenase with kinetic isotope effects and NMR determination of the hydride transfer stereospecificity. Arch. Biochem. Biophys. 348(2), 378-382 (1997).
41. Hedstrom L, Gan L, Schlippe G, Riera T, Seyedsayamdost M. IMP dehydrogenase: the dynamics of drug selectivity. Nucleic Acids Res. (Suppl. 3) 97-98 (2003).
42. Guillen Schlippe YV, Hedstrom L. A twisted base? The role of arginine in enzyme-catalyzed proton abstractions. Arch. Biochem. Biophys. 433(1), 266-278 (2005).
43. Min D, Josephine HR, Li H et al. An enzymatic atavist revealed in dual pathways for water activation. PLoS Biol. 6(8), 1802-1810 (2008).
44. Guillen Schlippe YV, Riera TV, Seyedsayamdost MR, Hedstrom L. Substitution of the conserved Arg-Tyr dyad selectively disrupts the hydrolysis phase of the IMP dehydrogenase reaction. Biochemistry 43(15), 4511-4521 (2004).
45. Guillen Schlippe YV, Hedstrom L. Is Arg-418 the catalytic base required for the hydrolysis step of the IMP dehydrogenase reaction? Biochemistry 44(35), 11700-11707 (2005).
46. Guillen Schlippe YV, Hedstrom L. Guanidine derivatives rescue the Arg-418-Ala mutation of tritrichomonas foetus IMP dehydrogenase. Biochemistry 44(50), 16695-16700 (2005).
47. Lander ES, Linton LM, Birren B et al. Initial sequencing and analysis of the human genome. Nature 409(6822), 860-921 (2001).
48. Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S. Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Lett. 523(1-3), 257 (2002).
49. Filmore D. It's a GPCR world. Mod. Drug Discovery, 7(11), 24-28 (2004).
50. Lanford RE, Chavez D, Guerra B et al. Ribavirin induces error-prone replication of GB virus B in primary tamarin hepatocytes. J. Virol. 75(17), 8074-8081 (2001).
51. Saunders JO, Raybuck SA. Chapter 18. Inosine monophosphate dehydrogenase: consideration of structure, kinetics, and therapeutic potential. Annu. Rep. Med. Chem. 35, 201-210 (2000).
52. Pankiewicz KW. Inhibitors of inosine monophosphate dehydrogenase as potential chemotherapeutic agents. Expert Opin. Ther. Pat. 11(7), 1161-1170 (2001).
53. Guidicelli G, Chaigne-Delalande B, Dilhuydy M-S et al. The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells. PLoS One 4(5), e5493 (2009).
54. Pankiewicz KW, Patterson SE, Black PL et al. Cofactor mimics as selective inhibitors of NAD-dependent inosine monophosphate dehydrogenase (IMPDH) - the major therapeutic target. Curr. Med. Chem. 11(7), 887-900 (2004).
55. Jain J, Almquist SJ, Shlyakhter D, Harding MW. VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent. J. Pharm. Sci. 90(5), 625-637 (2001).
56. Chen L, Wilson D, Jayaram HN, Pankiewicz KW. Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylases for cancer treatment. J. Med. Chem. 50(26), 6685-6691 (2007).
57. Bremer S, Vethe NT, Rootwelt H et al. Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. J. Transl. Med. 7, 64 (2009).
58. Liu Y, Bohn SA, Sherley JL. Inosine-5́- monophosphate dehydrogenase is a rate-determining factor for p53-dependent growth regulation. Mol. Biol. Cell, 9(1), 15-28 (1998).
59. Dalal P, Grafals M, Chhabra D, Gallon L. Mycophenolate mofetil: safety and efficacy in the prophylaxis of acute kidney transplantation rejection. Ther. Clin. Risk Manage. 5, 139-149 (2009).
60. Chaigne-Delalande B, Guidicelli G, Couzi L et al. The immunosuppressor mycophenolic acid kills activated lymphocytes by inducing a nonclassical actin-dependent necrotic signal. J. Immunol. 181(11), 7630-7638 (2008).
61. Haessler J, Shaughnessy JD Jr, Zhan F et al. Benefit of complete response in multiple myeloma limited to high-risk subgroup identified by gene expression profiling. Clin. Cancer Res. 13(23), 7073-7079 (2007).
62. Oravecz-Wilson KI, Philips ST, Yilmaz OH et al. Persistence of leukemia-initiating cells in a conditional knockin model of an imatinib-responsive myeloproliferative disorder. Cancer Cell 16(2), 137-148 (2009).
63. Bonnet D. Normal and leukaemic stem cells. Br. J. Haematol. 130(4), 469-479 (2005).
64. Everts S. Getting to the root of cancer. Chem. Eng. News, 85, 28-29 (2007).
65. Inai K, Tsutani H, Yamauchi T, Nakamura T, Ueda T. Differentiation and reduction of intracellular GTP levels in HL-60 and U937 cells upon treatment with IMP dehydrogenase inhibitors. Adv. Exp. Med. Biol. 431, 549-553 (1998).
66. Inai K, Tsutani H, Yamauchi T et al. Differentiation induction in nonlymphocytic leukemia cells upon treatment with mycophenolate mofetil. Leuk. Res. 24(9), 761-768 (2000).
67. Gu JJ, Santiago L, Mitchell BS. Synergy between imatinib and mycophenolic acid in inducing apoptosis in cell lines expressing Bcr-Abl. Blood 105(8), 3270-3277 (2005).
68. Rambhatla L, Ram-Mohan S, Cheng JJ, Sherley JL. Immortal DNA strand cosegregation requires p53/ IMPDH-dependent asymmetric self-renewal associated with adult stem cells. Cancer Res. 65(8), 3155-3161 (2005).
69. Floryk D, Thompson TC. Antiproliferative effects of AVN944, a novel inosine 5́-monophosphate dehydrogenase inhibitor, in prostate cancer cells. Int. J. Cancer 123(10), 2294-2302 (2008).
70. Hamilton JM, Harding MW, Genna T, Bol DK. A phase I dose-ranging study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of AVN944, an IMPDH inhibitor, in healthy male volunteers. J. Clin. Pharmacol. 49(1), 30-38 (2009).
71. Fagbami A, Halstead SB, Marchette N, Larsen K. Heterologous flavivirus infection-enhancing antibodies in sera of Nigerians. Am. J. Trop. Med. Hyg. 38(1), 205-207 (1988).
72. Halstead SB. Pathogenesis of dengue: challenges to molecular biology. Science 239(4839), 476-481 (1988).
73. Nair V, Chi G, Shu Q, Julander J, Smee DF. A heterocyclic molecule with significant activity against dengue virus. Bioorg. Med. Chem. Lett. 19(5), 1425-1427 (2009).
74. Nair V, Uchil V, Ma X, Zhu Q, Zhang F, Bonsu E. Ribonucleosides bearing Michael acceptors: synthesis, molecular docking, enzyme inhibition data and antiviral activity. Nucleic Acids Symp. Ser. (52), 625-626 (2008).
75. Nair V, Ma X, Shu Q, Zhang F, Uchil V, Cherukupalli Govardhan R. IMPDH as a biological probe for RNA antiviral drug discovery: synthesis, enzymology, molecular docking, and antiviral activity of new ribonucleosides with surrogate bases. Nucleosides Nucleotides Nucleic Acids 26(6-7), 651-654 (2007).
76. Pal S, Bera B, Nair V. Inhibition of inosine monophosphate dehydrogenase (IMPDH) by the antiviral compound, 2-vinylinosine monophosphate. Bioorg. Med. Chem. 10(11), 3615-3618 (2002).
77. Gottlieb S. Hepatitis C infects almost 2% of US population. BMJ 319, 535 (1999).
78. Marcellin P, Horsmans Y, Nevens F et al. Phase 2 study of the combination of merimepodib with peginterferon-α2b, and ribavirin in nonresponders to previous therapy for chronic hepatitis C. J. Hepatol. 47(4), 476-483 (2007).
79. Markland W, McQuaid TJ, Jain J, Kwong AD. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with a interferon. Antimicrob. Agents Chemother. 44(4), 859-866 (2000).
80. Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc. Natl Acad. Sci. USA 98(12), 6895-6900 (2001).
81. Zhou S, Liu R, Baroudy BM, Malcolm BA, Reyes GR. The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA. Virology 310(2), 333-342 (2003).
82. Wu JZ, Walker H, Lau JYN, Hong Z. Activation and deactivation of a broad-spectrum antiviral drug by a single enzyme: adenosine deaminase catalyzes two consecutive deamination reactions. Antimicrob. Agents Chemother. 47(1), 426-431 (2003).
83. Kearney KR, Thornton JJ, Navarro VJ. Taribavirin for the treatment of chronic hepatitis C. Expert Opin. Pharmacother. 9(18), 3243-3249 (2008).
84. Wu JZ, Larson G, Hong Z. Dual-action mechanism of viramidine functioning as a prodrug and as a catabolic inhibitor for ribavirin. Antimicrob. Agents Chemother. 48(10), 4006-4008 (2004).
85. Poordad FF, Chee G. Taribavirin: a potential alternative to ribavirin. Future Virol. 4(2), 113-120 (2009).
86. Tossing G. Merimepodib, Vertex. Drugs 6(4), 372-376 (2003).
87. Sorbera LA, Silvestre JS, Castaner J, Martin L. VX-497: anti-HCV antipsoriatic IMPDH inhibitor. Drugs Future 25(8), 809-814 (2000).
88. Spellicy CJ, Daiger SP, Sullivan LS et al. Characterization of retinal inosine monophosphate dehydrogenase 1 in several mammalian species. Mol. Vision 13, 1866-1872 (2007).
89. Nagai M, Natsumeda Y, Weber G. Proliferation-linked regulation of type II IMP dehydrogenase gene in human normal lymphocytes and HL-60 leukemic cells. Cancer Res. 52(2), 258-261 (1992).
90. Nagai M, Natsumeda Y, Konno Y, Hoffman R, Irino S, Weber G. Selective up-regulation of type II inosine 5́-monophosphate dehydrogenase messenger RNA expression in human leukemias. Cancer Res. 51(15), 3886-3890 (1991).
91. Digits JA, Hedstrom L. Species-specific inhibition of inosine 5́-monophosphate dehydrogenase by mycophenolic acid. Biochemistry 38(46), 15388-15397 (1999).
92. Maurya SK, Gollapalli DR, Kirubakaran S et al. Triazole inhibitors of Cryptosporidium parvum inosine 5́-monophosphate dehydrogenase. J. Med. Chem. 52(15), 4623-4630 (2009).
93. Digits JA, Hedstrom L. Drug selectivity is determined by coupling across the NAD+ site of IMP dehydrogenase. Biochemistry 39(7), 1771-1777 (2000).
94. Umejiego NN, Gollapalli D, Sharling L et al. Targeting a prokaryotic protein in a eukaryotic pathogen: identification of lead compounds against cryptosporidiosis. Chem. Biol. 15(1), 70-77 (2008).
95. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282(7), 677-686 (1999).
96. Dye C, Espinal Marcos A, Watt Catherine J, Mbiaga C, Williams Brian G. Worldwide incidence of multidrug-resistant tuberculosis. J. Infect. Dis. 185(8), 1197-1202 (2002).
97. Wenner M. A new kind of drug target. Sci. Am. 301(2), 70-76 (2009).
98. Barnes BJ, Eakin AE, Izydore RA, Hall IH. Selective inhibition of human Molt-4 leukemia type II inosine 5'-monophosphate dehydrogenase by the 1,5-diazabicyclo[3.1.0] hexane-2,4-diones. Biochemistry 39(45), 13641-13650 (2000).