Assessment of drug candidates for broad-spectrum antiviral therapy targeting cellular pyrimidine biosynthesis

Antiviral Research

Volumn 100, Issue 3, 2013, Pages 640-648

  Marschall, Manfred ^a   Niemann, Ina ^a   Kosulin, Karin ^b   Bootz, Anna ^a   Wagner, Sabrina ^a   Dobner, Thomas ^b   Herz, Thomas ^c   Kramer, Bernd ^c   Leban, Johann ^c   Vitt, Daniel ^c   Stamminger, Thomas ^a   Hutterer, Corina ^a   Strobl, Stefan ^c  

^a UNIVERSITY OF ERLANGEN NUREMBERG   (Germany)

^b LEIBNIZ INSTITUTE FOR EXPERIMENTAL VIROLOGY   (Germany)

^c 4SC AG   (Germany)

Author keywords

4SCan drug design; Antiviral drug candidate; Broad spectrum antiviral therapy; Cytomegaloviruses and adenoviruses; Pyrimidine biosynthesis; Target dihydroorotate dehydrogenase

Indexed keywords

3 (2,3,5,6 TETRAFLUORO 3' TRIFLUOROMETHOXY BIPHENYL 4 YLCARBAMOYL) THIOPHENE 2 CARBOXYLIC ACID; ANTIVIRUS AGENT; CARBOXYLIC ACID DERIVATIVE; DIHYDROOROTATE DEHYDROGENASE; GANCICLOVIR; OROTIC ACID; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG; URACIL; URIDINE; ANTIMETABOLITE; ENZYME INHIBITOR; OXIDOREDUCTASE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL ACTIVITY; ANTIVIRAL SUSCEPTIBILITY; ANTIVIRAL THERAPY; ARTICLE; COMPUTER MODEL; CONTROLLED STUDY; CRYSTALLIZATION; CYTOMEGALOVIRUS; DRUG DESIGN; DRUG EFFICACY; DRUG SALIVA LEVEL; DRUG SYNTHESIS; DRUG TARGETING; EMBRYO; ENZYME ACTIVITY; ENZYME INHIBITION; EPSTEIN BARR VIRUS; FIBROBLAST; GENE EXPRESSION; HERPES SIMPLEX VIRUS 1; HERPES SIMPLEX VIRUS 2; HUMAN; HUMAN ADENOVIRUS 2; HUMAN CELL; HUMAN CYTOMEGALOVIRUS; HUMAN HERPESVIRUS 6; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PRECURSOR; PRIORITY JOURNAL; PYRIMIDINE SYNTHESIS; VACCINIA VIRUS; VARICELLA ZOSTER VIRUS; VIRUS REPLICATION; 4SCAN DRUG DESIGN; ANIMAL; ANTIVIRAL DRUG CANDIDATE; BIOSYNTHESIS; BROAD-SPECTRUM ANTIVIRAL THERAPY; CELL CULTURE; CHEMICAL STRUCTURE; CHEMISTRY; COMPUTER SIMULATION; CYTOMEGALOVIRUSES AND ADENOVIRUSES; DRUG ANTAGONISM; DRUG EFFECT; DRUG SCREENING; ENZYMOLOGY; GERMFREE ANIMAL; HERPES VIRUS; HUMAN ADENOVIRUS; METHODOLOGY; STRUCTURE ACTIVITY RELATION; SYNTHESIS; TARGET DIHYDROOROTATE DEHYDROGENASE; VIROLOGY; VIRUS CULTURE; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; HERPESVIRIDAE; IC50; PROCEDURES;

ANIMALIA; HUMAN HERPESVIRUS 5; MURID HERPESVIRUS 1;

4SCAN DRUG DESIGN; ANTIVIRAL DRUG CANDIDATE; BROAD-SPECTRUM ANTIVIRAL THERAPY; CYTOMEGALOVIRUSES AND ADENOVIRUSES; PYRIMIDINE BIOSYNTHESIS; TARGET DIHYDROOROTATE DEHYDROGENASE;

ADENOVIRUSES, HUMAN; ANIMALS; ANTIMETABOLITES; ANTIVIRAL AGENTS; CELLS, CULTURED; COMPUTER SIMULATION; CYTOMEGALOVIRUS; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; FIBROBLASTS; GANCICLOVIR; HERPESVIRIDAE; HUMANS; INHIBITORY CONCENTRATION 50; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; OXIDOREDUCTASES ACTING ON CH-CH GROUP DONORS; PYRIMIDINES; SPECIFIC PATHOGEN-FREE ORGANISMS; STRUCTURE-ACTIVITY RELATIONSHIP; VACCINIA VIRUS; VIRUS CULTIVATION;

EID: 84887058080     PISSN: 01663542     EISSN: 18729096     Source Type: Journal    
DOI: 10.1016/j.antiviral.2013.10.003     Document Type: Article

References (43)

1. G. Andrei, E. De Clercq, and R. Snoeck Drug targets in cytomegalovirus infection Infect. Disord. Drug Targets 9 2009 201 222
2. R.K. Avery, S.B. Mossad, E. Poggio, M. Lard, M. Budev, B. Bolwell, W.J. Waldman, W. Braun, S.D. Mawhorter, R. Fatica, V. Krishnamurthi, J.B. Young, R. Shrestha, B. Stephany, N. Lurain, and B. Yen-Lieberman Utility of leflunomide in the treatment of complex cytomegalovirus syndromes Transplantation 90 2010 419 426
3. S. Becke, V. Fabre-Mersseman, S. Aue, S. Auerochs, T. Sedmak, U. Wolfrum, D. Strand, M. Marschall, B. Plachter, and S. Reyda Modification of the major tegument protein pp65 of 1 human cytomegalovirus inhibits viral growth and leads to the enhancement of a protein complex with pUL69 and pUL97 in infected cells J. Gen. Virol. 91 2010 2531 2541
4. F.C. Breedveld, and J.M. Dayer Leflunomide: mode of action in the treatment of rheumatoid arthritis Ann. Rheum. Dis. 59 2000 841 849
5. B. Chacko, and G.T. John Leflunomide for cytomegalovirus: bench to bedside Transpl. Infect. Dis. 14 2012 111 120
6. S. Chou, G. Marousek, S. Auerochs, T. Stamminger, J. Milbradt, and M. Marschall The unique antiviral activity of artesunate is broadly effective against human cytomegaloviruses including therapy-resistant mutants Antiviral Res. 92 2011 364 368
7. J.P. Davis, G.A. Cain, W.J. Pitts, R.L. Magolda, and R.A. Copeland The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase Biochemistry 35 1996 1270 1273 (Pubitemid 26050790)
8. M.M. Goldenberg Leflunomide, a novel immunomodulator for the treatment of active rheumatoid arthritis Clin. Ther. 21 1999 1837 1852
9. A.F. Henao-Martínez, A. Weinberg, W.J. Waldman, and M.E. Levi Successful treatment of acyclovir-resistant herpes simplex virus type 2 proctitis with leflunomide in an HIV-infected man J. Clin. Virol. 54 2012 276 278
10. M.L. Herrmann, R. Schleyerbach, and B.J. Kirschbaum Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases Immunopharm 47 2000 273 289 (Pubitemid 30394543)
11. T. Herz, K. Wolf, J. Kraus, and B. Kramer 4SCan/vADME: intelligent library screening as a shortcut from hits to lead compounds Expert Opin. Drug Metab. Toxicol. 2 2006 471 484 (Pubitemid 46141410)
12. A.J. Hume, J.S. Finkel, J.P. Kamil, D.M. Coen, M.R. Culbertson, and R.F. Kalejta Phosphorylation of retinoblastoma protein by viral protein with cyclin-dependent kinase function Science 320 2008 797 799 (Pubitemid 351929629)
13. C. Hutterer, S.K. Wandinger, S. Wagner, R. Müller, T. Stamminger, I. Zeitträger, K. Godl, R. Baumgartner, S. Strobl, and M. Marschall Profiling of the kinome of cytomegalovirus-infected cells reveals the functional importance of host kinases Aurora A, ABL and AMPK Antiviral Res. 99 2013 139 148
14. J.E. Hyde Targeting purine and pyrimidine metabolism in human apicomplexan parasites Curr. Drug Targets 8 2007 31 47 (Pubitemid 46043897)
15. G.T. John, J. Manivannan, S. Chandy, S. Peter, and C.K. Jacob Leflunomide therapy for cytomegalovirus disease in renal allograft recepients Transplantation 77 2004 1460 1461 (Pubitemid 38668445)
16. K. Kindsmüller, S. Schreiner, F. Leinenkugel, P. Groitl, E. Kremmer, and T. Dobner A 49-kilodalton isoform of the adenovirus type 5 early region 1B 55-kilodalton protein is sufficient to support virus replication J. Virol. 83 2009 9045 9056
17. K. Klenovsek, F. Weisel, A. Schneider, U. Appelt, S. Jonjic, M. Messerle, B. Bradel-Tretheway, T.H. Winkler, and M. Mach Protection from CMV infection in immunodeficient hosts by adoptive transfer of memory B cells Blood 110 2007 3472 3479 (Pubitemid 350106344)
18. J. Leban, M. Kralik, J. Mies, R. Baumgartner, M. Gassen, and S. Tasler Biphenyl-4-ylcarbamoyl thiophene carboxylic acids as potent DHODH inhibitors Bioorg. Med. Chem. Lett. 15 2006 267 270 (Pubitemid 41680610)
19. P. Lischka, and H. Zimmermann Antiviral strategies to combat cytomegalovirus infections in transplant recipients Curr. Opin. Pharmacol. 8 2008 541 548
20. S. Liu, E.A. Neidhardt, T.H. Grossman, T. Ocain, and J. Clardy Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents Structure 8 2000 25 33 (Pubitemid 30051339)
21. M. Marschall, and T. Stamminger Molecular targets for antiviral therapy of cytomegalovirus infections Future Microbiol. 4 2009 731 742
22. M. Marschall, M. Freitag, S. Weiler, G. Sorg, and T. Stamminger Recombinant green fluorescent protein-expressing human cytomegalovirus as a tool for screening antiviral agents Antimicrob. Agents Chemother. 44 2000 1588 1597 (Pubitemid 30340800)
23. M. Marschall, T. Stamminger, A. Urban, S. Wildum, H. Ruebsamen-Schaeff, H. Zimmermann, and P. Lischka In vitro evaluation of the activities of the novel anti-cytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses Antimicrob. Agents Chemother. 56 2012 1135 1137
24. E.S. Mocarski, T. Shenk, and R.F. Pass Cytomegaloviruses D.M. Knipe, P.M. Howley, Fields Virology fifth ed. 2007 Lippincott Williams & Wilkins Wolters Kluwer 2701 2772
25. H. Munier-Lehmann, P.O. Vidalain, F. Tangy, and Y.L. Janin On dihydroorotate dehydrogenases and their inhibitors and uses J. Med. Chem. 56 2013 3148 3167
26. N.J. Olsen, and C.M. Stein New drugs for rheumatoid arthritis N. Engl. J. Med. 350 2004 2167 2179
27. G.J. Peters, J.C. Schwartsmann, E.J. Nadal, E.J. Laurensse, C.J. van Groeningen, W.J.F. van der Vijgh, and H.M. Pinedo In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients Cancer Res. 50 1990 4644 4649 (Pubitemid 20230407)
28. M.A. Phillips, and P.K. Rathod Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy Infect. Disord. Drug Targets 10 2010 226 239
29. D. Pytel, T. Sliwinski, T. Poplawski, D. Ferriola, and I. Majsterek Tyrosine kinase blockers: new hope for successful cancer therapy Anticancer Agents Med. Chem. 9 2009 66 76
30. S. Rechter, T. König, S. Auerochs, S. Thulke, H. Walter, H. Dornenburg, C. Walter, and M. Marschall Antiviral activity of Arthrospira-derived spirulan-like substances Antiviral Res. 72 2006 197 206 (Pubitemid 44708302)
31. D.D. Richman Antiviral drug resistance Antiviral Res. 71 2006 117 121 (Pubitemid 44223755)
32. K. Rückemann, L.D. Fairbanks, E.A. Carrey, C.M. Hawrylowicz, D.F. Richards, B. Kirschbaum, and H.A. Simmonds Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans J. Biol. Chem. 273 1998 21682 21691 (Pubitemid 28405342)
33. M. Schleiss, J. Eickhoff, S. Auerochs, M. Leis, S. Abele, S. Rechter, Y. Choi, J. Anderson, G. Scott, W. Rawlinson, D. Michel, S. Ensminger, B. Klebl, T. Stamminger, and M. Marschall Protein kinase inhibitors of the quinazoline class exert anti-cytomegaloviral activity in vitro and in vivo Antiviral Res. 79 2008 49 61
34. M.H.J. Seifert, F. Schmitt, T. Herz, and B. Kramer ProPose: a docking engine based on a fully configurable protein-ligand interaction model J. Mol. Model. 10 2004 342 357 (Pubitemid 40012063)
35. C. Steininger Novel therapies for cytomegalovirus disease Recent Pat. Antiinfect. Drug Discov. 2 2007 53 72 (Pubitemid 46729087)
36. S. Tasler, J. Kraus, A. Wuzik, O. Müller, A. Aschenbrenner, E. Cubero, R. Pascual, J.R. Quintana-Ruiz, A. Dordal, R. Mercè, and X. Codony Discovery of 5-HT6 receptor ligands based on virtual HTS Bioorg. Med. Chem. Lett. 17 2007 6224 6229 (Pubitemid 47552822)
37. S. Tasler, O. Müller, T. Wieber, T. Herz, R. Krauss, F. Totzke, M.H. Kubbutat, and C. Schächtele N-substituted 2′-(aminoaryl) benzothiazoles as kinase inhibitors: hit identification and scaffold hopping Bioorg. Med. Chem. Lett. 19 2009 1349 1356
38. M. Thomas, S. Rechter, J. Milbradt, S. Auerochs, R. Müller, T. Stamminger, and M. Marschall Cytomegaloviral protein kinase pUL97 interacts with the nuclear mRNA export factor pUL69 to modulate its intranuclear localization and activity J. Gen. Virol. 90 2009 567 578
39. V.K. Vyas, and M. Ghaté Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors Mini Rev. Med. Chem. 11 2011 1039 1055
40. W.J. Waldman, D.A. Knight, L. Blinder, J. Shen, N.S. Lurain, D.M. Miller, D.D. Sedmak, J.W. Williams, and A.S. Chong Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide Intervirology 42 1999 412 418 (Pubitemid 30122078)
41. W.J. Waldman, D.A. Knight, N.S. Lurain, D.M. Miller, D.D. Sedmak, J.W. Williams, and A.S. Chong Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide Transplantation 68 1999 814 825 (Pubitemid 29468200)
42. Q.Y. Wang, S. Bushell, M. Qing, H.Y. Xu, A. Bonavia, S. Nunes, J. Zhou, M.K. Poh, P. Florez de Sessions, P. Niyomrattanakit, H. Dong, K. Hoffmaster, A. Goh, S. Nilar, W. Schul, S. Jones, L. Kramer, T. Compton, and P.Y. Shi Inhibition of dengue virus through suppression of host pyrimidine biosynthesis J. Virol. 85 2011 6548 6556
43. R. Webel, J. Milbradt, S. Auerochs, V. Schregel, C. Held, K. Nöbauer, E. Razzazi-Fazeli, C. Jardin, T. Wittenberg, H. Sticht, and M. Marschall Two isoforms of the protein kinase pUL97 of human cytomegalovirus are differentially regulated in their nuclear translocation J. Gen. Virol. 92 2011 638 649