The structure of inosine 5'-monophosphate dehydrogenase and the design of novel inhibitors

Immunopharmacology

Volumn 47, Issue 2-3, 2000, Pages 163-184

  Sintchak, Michael D ^a   Nimmesgern, Elmar ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

Autoimmune diseases; Inosine 5' monophosphate dehydrogenase; Novel inhibitors

Indexed keywords

ENZYME INHIBITOR; IMMUNOSUPPRESSIVE AGENT; INOSINATE DEHYDROGENASE; INOSINE PHOSPHATE; MERIMEPODIB; UNCLASSIFIED DRUG;

AUTOIMMUNE DISEASE; CRYSTAL STRUCTURE; DRUG DEVELOPMENT; ENZYME ACTIVITY; ENZYME CONFORMATION; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; PRIORITY JOURNAL; REVIEW;

EID: 0034121721     PISSN: 01623109     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0162-3109(00)00193-4     Document Type: Article

References (84)

1. Allison A.C., Hovi T., Watts R.W.E., Webster A.D.B. The role of de novo purine synthesis in lymphocyte transformation. Ciba Found. Symp. 48:1977;207-224.
2. Allison A.C., Eugui E.M. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 47:2000;. in press.
3. Almquist S.J., Shlyakhter D., Harding M.W., Jain J. VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent. XVII World Congress of the Transplant Society, Montreal:1998;. (abstract).
4. Amzel L.M. Structure-based drug design. Curr. Opin. Biotechnol. 9:1998;366-369.
5. Anderson W.K., Boehm T.L., Makara G.M., Swann R.T. Synthesis and modeling studies with monocyclic analogues of mycophenolic acid. J. Med. Chem. 39:1996;46-55.
6. Antonino L.C., Straub K., Wu J.C. Probing the active site of human IMP dehydrogenase using halogenated purine riboside 5′-monophosphates and covalent modification reagents. Biochemistry. 33:1994;1760-1765.
7. Bateman A. The structure of a domain common to archaebacteria and the homocysteinuria disease protein. Trends Biochem. Sci. 22:1997;12-13.
8. Balzarini J., Karlsson A., Wang L., Bohman C., Horska K., Votruba I., Fridland A., Van Aerschot A., Herdewijn P., De Clercq E. EICAR (5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide). A novel potent inhibitor of inosinate dehydrogenase activity and guanylate biosynthesis. J. Biol. Chem. 268:1993;24591-24598.
9. Bemis G.W., Kuntz I.D. A fast and efficient method of 2D and 3D molecular shape description. J. Comput.-Aided Mol. Des. 6:1992;607-628.
10. Berman J.D., Webster H.K. In vitro effects of mycophenolic acid and allopurinol against Leishmania tropica in human macrophages. Antimicrob. Agents Chemother. 21:1982;887-891.
11. Borel J.F., Kis Z.L. The discovery and development of cyclosporine (Sandimmune). Transplant. Proc. 23:1991;1867-1874.
12. Bullingham R.E.S., Nicholls A.J., Kamm B.R. Clinical pharmacokinetics of mycophenolate mofetil. Clin. Pharmacokinet. 34:1998;429-455.
13. Carr S.F., Papp E., Wu J.C., Natsumeda Y. Characterization of human type I and type II IMP dehydrogenases. J. Biol. Chem. 268:1993;27286-27290.
14. Carson M. Ribbons 2.0. J. Appl. Crystallogr. 24:1991;958-961.
15. Carter S.B., Franklin T.J., Jones D.F., Leonard B.J., Mills S.D., Turner R.W., Turner W.B. Mycophenolic acid: an anti-cancer compound with unusual properties. Nature. 223:1969;848-850.
16. Colby T.D., Vanderveen K., Strickler M.D., Markham G.D., Goldstein B.M. Crystal structure of human type II inosine monophosphate dehydrogenase: implications for ligand binding and drug design. Proc. Natl. Acad. Sci. U. S. A. 96:1999;3531-3536.
17. Collart F.R., Huberman E. Cloning and sequence analysis of the human and Chinese hamster inosine-5'-monophosphate dehydrogenase cDNAs. J. Biol. Chem. 263:1988;15769-15772.
18. + with potent IMP dehydrogenase-inhibitory properties. Biochem. Pharmacol. 31:1982;2133-31236.
19. Davis G.L., Esteban-Mur R., Rustgi V., Hoefs J., Gordon S.C., Trepo C., Shiffman M.L., Zeuzem S., Craxi A., Ling M.H., Albrecht J. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N. Engl. J. Med. 339:1998;1493-1499.
20. Decker C.J., Heiser A.D., Faust T., Ku G., Mosely S., Nimmesgern E. The novel IMPDH inhibitor VX-497 prolongs skin graft survival and improves GvHD in mouse. Transplantation. 67:1999;S57. (abstract).
21. Eugui E.M., Almquist S.J., Muller C.D., Allison A.C. Lymphocyte-selective cytostatic and immunosuppressive effects of mycophenolic acid in vitro: role of deoxyguanosine nucleotide depletion. Scand. J. Immunol. 33:1991;161-173.
22. Farazi T., Leichman J., Harris T., Cahoon M., Hedstrom L. Isolation and characterization of mycophenolic acid-resistant mutants of inosine-5'-monophosphate dehydrogenase. J. Biol. Chem. 272:1997;961-965.
23. Fleming M.A., Chambers S.P., Connelly P.R., Nimmesgern E., Fox T., Bruzzese F.J., Hoe S.T., Fulghum J.R., Livingston D.J., Stuver C.M., Sintchak M.D., Wilson K.P., Thomson J.A. Inhibition of IMPDH by mycophenolic acid: dissection of forward and reverse pathways using capillary electrophoresis. Biochemistry. 35:1996;6990-6997.
24. Franklin T.J., Cook J.M. The inhibition of nucleic acid synthesis by mycophenolic acid. Biochem. J. 113:1969;515-524.
25. Franklin T.J., Morris W.P. Pharmacodynamics of the inhibition of GTP synthesis in vivo by mycophenolic acid. Adv. Enzyme Regul. 34:1994;107-117.
26. Franklin T.J., Jacobs V.N., Jones J., Ple P. Human colorectal carcinoma cells in vitro as a means to assess the metabolism of analogs of mycophenolic acid. Drug Metab. Dispos. 25:1997;367-370.
27. Gosio B. Richerche batteriologiche e chimiche sulle alterazioni del mais. Riv. Ig. Sanita Pubblica Ann. 7:1896;825-849.
28. Gummert J.F., Barten M.J., Boeke K., Leon E.J., Decker C.J., Nimmesgern E., Billingham M.E., Morris R.E. The IMPDH inhibitor VX-497 is the first rationally synthesized immunosuppressant to prolong allograft survival. Transplantation. 67:1999;S62. (abstract).
29. Hedstrom L., Wang C.C. Mycophenolic acid and adenine dinucleotide inhibition of Tritrichomonas foetus inosine 5'-monophosphate dehydrogenase: implications on enzyme mechanism. Biochemistry. 29:1990;849-854.
30. Herrmann M.L., Schleyerbach R., Kirschbaum B.J. Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 47:2000;273-289.
31. Holmes E.W., Pehlke D.M., Kelley W.N. Human IMP dehydrogenase. Kinetics and regulatory properties. Biochim. Biophys. Acta. 364:1974;209-217.
32. Huete-Pérez J.A., Wu J.C., Whitby F.G., Wang C.C. Identification of the IMP binding site in the IMP dehydrogenase from Tritrichomonas foetus. Biochemistry. 34:1995;13889-13894.
33. Hupe D.J., Azzolina B.A., Behrens N.D. IMP dehydrogenase from the intracellular parasitic protozoan Eimeria tenella and its inhibition by mycophenolic acid. J. Biol. Chem. 261:1986;8363-8369.
34. Jackson R.C., Weber G., Morris H.P. IMP dehydrogenase, an enzyme linked with proliferation and malignancy. Nature. 256:1975;331-333.
35. Jarvis R.A., Patrick E.A. Clustering using a similarity measure based on shared near neighbors. IEEE Trans. Comput. C-22(11):1973;1025-1034.
36. Keown K.et al. A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation. 61:1996;1029-1037.
37. Kobashigawa J., Miller L., Renlund D., Mentzer R., Alderman E., Bourge R., Costanzo M., Eisen H., Dureau G., Ratkovec R., Hummel M., Ipe D., Johnson J., Keogh A., Mamelok R., Mancini D., Smart F., Valantine H. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation. 66:1998;507-515.
38. Kornberg A., Baker T.A. DNA Replication. 1992;Freeman, New York.
39. Kuntz I.D., Blaney J.M., Oatley S.J., Langridge R., Ferrin T.E. A geometric approach to macromolecule-ligand interactions. J. Mol. Biol. 161:1982;269-288.
40. Kusumi T., Tsuda M., Katsunuma T., Yamamura M. Dual inhibitory effect of bredinin. Cell Biochem. Funct. 7:1988;201-204.
41. Kwong A.D. VX-497, a novel IMPDH inhibitor, is a broad spectrum antiviral agent with superior activity compared to ribavirin against selected DNA and RNA viruses in vitro. The XII International Conference on Antiviral ResearchJerusalem. vol. 18:1999;. (abstract).
42. Lesiak K., Watanabe K.A., Majumdar A., Powell J., Seidman M., Vanderveen K., Goldstein B.M., Pankiewicz K.W. Synthesis of a methylenebis (phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD. J. Med. Chem. 41:1998;618-622.
43. Lightfoot T., Snyder F.F. Gene amplification and dual point mutations of mouse IMP dehydrogenase associated with cellular resistance of mycophenolic acid. Biochem. Biophys. Acta. 1217:1994;156-162.
44. Link J.O., Straub K. Trapping of an IMP dehydrogenase-substrate covalent intermediate by mycophenolic acid. J. Am. Chem. Soc. 118:1996;2091-2992.
45. Liu J. FK506 and cyclosporin: molecular probes for studying intracellular signal transduction. Trends Pharmacol. Sci. 14:1993;182-188.
46. Matsuda S., Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 47:2000;119-125.
47. McHutchison J.G., Gordon S.C., Schiff E.R., Shiffman M.L., Lee W.M., Rustgi V.K., Goodman Z.D., Ling M.H., Cort S., Albrecht J.K. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N. Engl. J. Med. 339:1998;1485-1492.
48. Mitsui A., Suzuki S. Immunosuppressive effect of mycophenolic acid. J. Antibiot. 22:1969;358-363.
49. Mizuno K., Tsujino M., Takada M., Hayashi M., Atsumi K. Studies on bredinin: I. Solation, characterization and biological properties. J. Antibiot. 27:1974;775-782.
50. Morris P.E. Jr., Montgomery J.A. Inhibitors of the enzyme purine nucleoside phosphorylase. Expert Opin. Ther. Patents. 8:1998;283-299.
51. Morris R.E. Mechanisms of action of new immunosuppressive drugs. Kidney Int. 49(Suppl. 53):1996;S26-S38.
52. Murcko M.A. Recent advances in ligand design methods. Lipkowitz K.B., Boyd D.B. Rev. Comput. Chem. 1997;1-66 Wiley-VCH, New York.
53. Natsumeda Y., Carr S.F. Human type I and type II IMP dehydrogenases as drug targets. Ann. N. Y. Acad. Sci. 696:1993;88-93.
54. Navia M.A. Protein drug complexes important for immunoregulation and organ transplantation. Curr. Opin. Struct. Biol. 6:1996;838-847.
55. Nelson P.H., Eugui E., Wang C.C., Allison A.C. Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid. J. Med. Chem. 33:1990;833-838.
56. Nelson P.H., Carr S.F., Devens B.H., Eugui E.M., Franco F., Gonzalez C., Hawley R.C., Loughhead D.G., Milan D.J., Papp E., Patterson J.W., Rouhafza S., Sjogren E.B., Smith D.B., Stephenson R.A., Talamas F.X., Waltos A.M., Weikert R.J., Wu J.C. Structure-activity relationships for inhibition of inosine monophosphate dehydrogenase by nuclear variants of mycophenolic acid. J. Med. Chem. 39:1996;4181-4196.
57. Neyts J., Meerbach A., McKenna P., De Clercq E. Use of the yellow fever virus vaccine strain 17D for the study of strategies for the treatment of yellow fever virus infections. Antiviral Res. 30:1996;125-132.
58. Nimmesgern E., Fox T., Fleming M.A., Thomson J.A. Conformational changes and stabilization of inosine 5′-monophosphate dehydrogenase associated with ligand binding and inhibition by mycophenolic acid. J. Biol. Chem. 271:1996;19421-19427.
59. Nimmesgern E., Black J., Futer O., Fulghum J.R., Chambers S.P., Brummel C.L., Raybuck S.A., Sintchak M.D. Biochemical analysis of the modular enzyme inosine 5′-monophosphate dehydrogenase. Protein Expression Purif. 17:2000;282-289.
60. Oliyaei A.J., de Mattos A.M., Bennet W.M. Pharmacology of immunosuppressive drugs. Drugs Today. 34:1998;463-479.
61. Pankiewicz K.W. Inhibitors of inosine monophosphate dehydrogenase as potential chemotherapeutic agents. Expert Opin. Ther. Patents. 9:1999;55-65.
62. Pichlmayr R.et al. Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. Lancet. 345:1995;1321-1325.
63. Poynard T., Marcellin P., Lee S.S., Niederau C., Minuk G.S., Ideo G., Bain V., Heathcote J., Zeuzem S., Trepo C., Albrecht J. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 352:1998;1426-1432.
64. Schalk-Hihi C., Zhang Y.-Z., Markham G.D. The conformation of NADH bound to inosine 5′-monophosphate dehydrogenase determined by transferred nuclear Overhauser effect spectroscopy. Biochemistry. 37:1998;7608-7616.
65. Schreiber S.L. Immunophilin-sensitive protein phosphatase action in cell signaling pathways. Cell. 70:1992;365-368.
66. Sidwell R.W., Huffman J.H., Khare G.P., Allen L.B., Witkowski J.T., Robbins R.K. Broad-spectrum antiviral activity of virazole: 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide. Science. 177:1972;705-706.
67. Silverman Kitchin J.E., Pomeranz M.K., Pak G., Washenik K., Shupack J.L. Rediscovering mycophenolic acid: a review of its mechanism, side effects, and potential uses. J. Am. Acad. Dermatol. 37:1997;445-449.
68. Sintchak M.D., Fleming M.A., Futer O., Raybuck S.A., Chambers S.P., Caron P.R., Murcko M.A., Wilson K.P. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid. Cell. 85:1996;921-930.
69. Sintchak M.D., Badia M.C., Futer O., Nimmesgern E. X-ray crystal structure of the antiviral drug ribavirin monophosphate bound to IMP dehydrogenase. The XII International Conference on Antiviral Research, Jerusalem. vol. 76:1999;. (abstract).
70. Sollinger H.W.et al. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation. 60:1995;225-232.
71. Spector T., Jones T.E., Miller R.L. Reaction mechanism and specificity of human GMP reductase. Substrates, inhibitors, activators, and inactivators. J. Biol. Chem. 254:1979;2308-2315.
72. Streeter D.G., Witkowski J.T., Khare G.P., Sidwell R.W., Bauer R.J., Robins R.K., Simon L.N. Mechanism of action of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole), a new broad-spectrum antiviral agent. Proc. Natl. Acad. Sci. U. S. A. 70:1973;1174-1178.
73. Suthanthiran M., Morris R.E., Strom T.B. Immunosuppressants: cellular and molecular mechanisms of action. Am. J. Kidney Dis. 28:1996;159-172.
74. Tricot G.J., Jayaram H.N., Lapis E., Natsumeda Y., Nichols C.R., Kneebone P., Heerema N., Weber G., Hoffman R. Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5′-phosphate dehydrogenase activity. Cancer Res. 49:1989;3696-3701.
75. Tricot G.J., Jayaram H.N., Weber G. Tiazofurin. Biological effects and clinical uses. Int. J. Cell Cloning. 8:1990;161-170.
76. Verham R., Meek T.D., Hedstrom L., Wang C.C. Purification, characterization, and kinetic analysis of inosine 5′-monophosphate dehydrogenase of Tritrichomonas foetus. Mol. Biochem. Parasitol. 24:1987;1-12.
77. Wang C.C., Verham R., Cheng H.W., Rice A., Wang A.L. Differential effects of inhibitors of purine metabolism on two trichomonad species. Biochem. Pharmacol. 33:1984;1323-1329.
78. Wang W., Papov V.V., Minakawa N., Matsuda A., Biemann K., Hedstrom L. Inactivation of inosine 5′-monophosphate dehydrogenase by the antiviral agent 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide 5′-monophosphate. Biochemistry. 35:1996;95-101.
79. Wang W., Hedstrom L. Kinetic mechanism of human inosine 5′-monophosphate dehydrogenase type II: random addition of substrates and ordered release of products. Biochemistry. 36:1997;8479-8483.
80. Wang W., Hedstrom L. A potent "fat base" nucleotide inhibitor of IMP dehydrogenase. Biochemistry. 37:1998;11949-11952.
81. Whitby F.G., Luecke H., Kuhn P., Somoza J.R, Huete-Perez J.A., Phillips J.D., Hill C.P., Fletterick R.J., Wang C.C. Crystal structure of Tritrichomonas foetus inosine-5′-monophosphate dehydrogenase and the enzyme-product complex. Biochemistry. 36:1997;10666-10674.
82. Williams R.H., Lively D.H., DeLong D.C., Cline J.C., Sweeny M.J. Mycophenolic acid: antiviral and antitumor properties. J. Antibiot. 21:1968;463-464.
83. Xiang B., Taylor J.C., Markham G.D. Monovalent cation activation and kinetic mechanism of inosine 5′-monophosphate dehydrogenase. J. Biol. Chem. 271:1996;1435-1440.
84. Zhang R.G., Evans G., Rotella E.J., Westbrook E.M., Beno D., Huberman E., Joachimiak A.J., Collart F.R. Characteristics and crystal structure of bacterial inosine-5′-monophosphate dehydrogenase. Biochemistry. 38:1999;4691-4700.