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. 1997 Jun;41(6):1220–1225. doi: 10.1128/aac.41.6.1220

SCH 48973: a potent, broad-spectrum, antienterovirus compound.

P J Buontempo 1, S Cox 1, J Wright-Minogue 1, J L DeMartino 1, A M Skelton 1, E Ferrari 1, R Albin 1, E J Rozhon 1, V Girijavallabhan 1, J F Modlin 1, J F O'Connell 1
PMCID: PMC163890  PMID: 9174174

Abstract

SCH 48973 is a novel molecule with potent, selective, antienterovirus activity. In assays of the cytopathic effect against five picornaviruses, SCH 48973 had antiviral activity (50% inhibitory concentrations [IC50s]) of 0.02 to 0.11 microg/ml, with no detectable cytotoxicity at 50 microg/ml. SCH 48973 inhibited 80% of 154 recent human enterovirus isolates at an IC50 of 0.9 microg/ml. The antiviral activity of SCH 48973 is derived from its specific interaction with viral capsid, as confirmed by competition binding studies. The affinity constant (Ki) for SCH 48973 binding to poliovirus was 8.85 x 10(-8) M. In kinetic studies, a maximum of approximately 44 molecules of SCH 48973 were bound to poliovirus capsid. SCH 48973 demonstrated efficacy in a murine poliovirus model of enterovirus disease. SCH 48973 increased the survival of infected mice when it was administered orally at dosages of 3 to 20 mg/kg of body weight/day. Oral administration of SCH 48973 also reduced viral titers in the brains of infected mice. On the basis of its in vitro and in vivo profiles, SCH 48973 represents a potential candidate for therapeutic intervention against enterovirus infections.

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Selected References

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  1. Andries K., Dewindt B., De Brabander M., Stokbroekx R., Janssen P. A. In vitro activity of R 61837, a new antirhinovirus compound. Arch Virol. 1988;101(3-4):155–167. doi: 10.1007/BF01310997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andries K., Dewindt B., Snoeks J., Willebrords R. Lack of quantitative correlation between inhibition of replication of rhinoviruses by an antiviral drug and their stabilization. Arch Virol. 1989;106(1-2):51–61. doi: 10.1007/BF01311037. [DOI] [PubMed] [Google Scholar]
  3. Badger J., Minor I., Kremer M. J., Oliveira M. A., Smith T. J., Griffith J. P., Guerin D. M., Krishnaswamy S., Luo M., Rossmann M. G. Structural analysis of a series of antiviral agents complexed with human rhinovirus 14. Proc Natl Acad Sci U S A. 1988 May;85(10):3304–3308. doi: 10.1073/pnas.85.10.3304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chapman M. S., Minor I., Rossmann M. G., Diana G. D., Andries K. Human rhinovirus 14 complexed with antiviral compound R 61837. J Mol Biol. 1991 Feb 5;217(3):455–463. doi: 10.1016/0022-2836(91)90749-v. [DOI] [PubMed] [Google Scholar]
  5. Cox S., Buontempo P. J., Wright-Minogue J., DeMartino J. L., Skelton A. M., Ferrari E., Schwartz J., Rozhon E. J., Linn C. C., Girijavallabhan V. Antipicornavirus activity of SCH 47802 and analogs: in vitro and in vivo studies. Antiviral Res. 1996 Oct;32(2):71–79. doi: 10.1016/0166-3542(95)00979-5. [DOI] [PubMed] [Google Scholar]
  6. Dagan R., Hall C. B., Powell K. R., Menegus M. A. Epidemiology and laboratory diagnosis of infection with viral and bacterial pathogens in infants hospitalized for suspected sepsis. J Pediatr. 1989 Sep;115(3):351–356. doi: 10.1016/s0022-3476(89)80831-5. [DOI] [PubMed] [Google Scholar]
  7. Diana G. D., McKinlay M. A., Brisson C. J., Zalay E. S., Miralles J. V., Salvador U. J. Isoxazoles with antipicornavirus activity. J Med Chem. 1985 Jun;28(6):748–752. doi: 10.1021/jm00383a010. [DOI] [PubMed] [Google Scholar]
  8. Eggers H. J., Koch M. A., Furst A., Daves G. D., Jr, Wilczynski J. J., Folkers K. Rhodanine: a selective inhibitor of the multiplication of echovirus 12. Science. 1970 Jan 16;167(3916):294–297. doi: 10.1126/science.167.3916.294. [DOI] [PubMed] [Google Scholar]
  9. Filman D. J., Syed R., Chow M., Macadam A. J., Minor P. D., Hogle J. M. Structural factors that control conformational transitions and serotype specificity in type 3 poliovirus. EMBO J. 1989 May;8(5):1567–1579. doi: 10.1002/j.1460-2075.1989.tb03541.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fox M. P., McKinlay M. A., Diana G. D., Dutko F. J. Binding affinities of structurally related human rhinovirus capsid-binding compounds are related to their activities against human rhinovirus type 14. Antimicrob Agents Chemother. 1991 Jun;35(6):1040–1047. doi: 10.1128/aac.35.6.1040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fox M. P., Otto M. J., McKinlay M. A. Prevention of rhinovirus and poliovirus uncoating by WIN 51711, a new antiviral drug. Antimicrob Agents Chemother. 1986 Jul;30(1):110–116. doi: 10.1128/aac.30.1.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Greve J. M., Davis G., Meyer A. M., Forte C. P., Yost S. C., Marlor C. W., Kamarck M. E., McClelland A. The major human rhinovirus receptor is ICAM-1. Cell. 1989 Mar 10;56(5):839–847. doi: 10.1016/0092-8674(89)90688-0. [DOI] [PubMed] [Google Scholar]
  13. Hayden F. G., Andries K., Janssen P. A. Safety and efficacy of intranasal pirodavir (R77975) in experimental rhinovirus infection. Antimicrob Agents Chemother. 1992 Apr;36(4):727–732. doi: 10.1128/aac.36.4.727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hierholzer J. C., Hilliard K. A., Esposito J. J. Serosurvey for "acute hemorrhagic conjunctivitis" virus (Enterovirus 70) antibodies in the Southeastern United States, with review of the literature and some epidemiologic implications. Am J Epidemiol. 1975 Dec;102(6):533–544. doi: 10.1093/oxfordjournals.aje.a112191. [DOI] [PubMed] [Google Scholar]
  15. Higgins P. G., Scott R. J., Davies P. M., Gamble D. R. A comparative study of viruses associated with acute haemorrhagic conjunctivitis. J Clin Pathol. 1974 Apr;27(4):292–296. doi: 10.1136/jcp.27.4.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hogle J. M., Chow M., Filman D. J. Three-dimensional structure of poliovirus at 2.9 A resolution. Science. 1985 Sep 27;229(4720):1358–1365. doi: 10.1126/science.2994218. [DOI] [PubMed] [Google Scholar]
  17. Ishitsuka H., Ohsawa C., Ohiwa T., Umeda I., Suhara Y. Antipicornavirus flavone Ro 09-0179. Antimicrob Agents Chemother. 1982 Oct;22(4):611–616. doi: 10.1128/aac.22.4.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jubelt B., Gallez-Hawkins G., Narayan O., Johnson R. T. Pathogenesis of human poliovirus infection in mice. I. Clinical and pathological studies. J Neuropathol Exp Neurol. 1980 Mar;39(2):138–148. doi: 10.1097/00005072-198003000-00003. [DOI] [PubMed] [Google Scholar]
  19. Kenny M. T., Dulworth J. K., Bargar T. M., Daniel J. K. Antipicornavirus activity of some diaryl methanes and aralkylaminopyridines. Antiviral Res. 1987 Feb;7(2):87–97. doi: 10.1016/0166-3542(87)90024-6. [DOI] [PubMed] [Google Scholar]
  20. Kim S. S., Smith T. J., Chapman M. S., Rossmann M. C., Pevear D. C., Dutko F. J., Felock P. J., Diana G. D., McKinlay M. A. Crystal structure of human rhinovirus serotype 1A (HRV1A). J Mol Biol. 1989 Nov 5;210(1):91–111. doi: 10.1016/0022-2836(89)90293-3. [DOI] [PubMed] [Google Scholar]
  21. McKinney R. E., Jr, Katz S. L., Wilfert C. M. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis. 1987 Mar-Apr;9(2):334–356. doi: 10.1093/clinids/9.2.334. [DOI] [PubMed] [Google Scholar]
  22. McSharry J. J., Caliguiri L. A., Eggers H. J. Inhibition of uncoating of poliovirus by arildone, a new antiviral drug. Virology. 1979 Sep;97(2):307–315. doi: 10.1016/0042-6822(79)90342-8. [DOI] [PubMed] [Google Scholar]
  23. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  24. Muckelbauer J. K., Kremer M., Minor I., Diana G., Dutko F. J., Groarke J., Pevear D. C., Rossmann M. G. The structure of coxsackievirus B3 at 3.5 A resolution. Structure. 1995 Jul 15;3(7):653–667. doi: 10.1016/s0969-2126(01)00201-5. [DOI] [PubMed] [Google Scholar]
  25. Oliveira M. A., Zhao R., Lee W. M., Kremer M. J., Minor I., Rueckert R. R., Diana G. D., Pevear D. C., Dutko F. J., McKinlay M. A. The structure of human rhinovirus 16. Structure. 1993 Sep 15;1(1):51–68. doi: 10.1016/0969-2126(93)90008-5. [DOI] [PubMed] [Google Scholar]
  26. Otto M. J., Fox M. P., Fancher M. J., Kuhrt M. F., Diana G. D., McKinlay M. A. In vitro activity of WIN 51711, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother. 1985 Jun;27(6):883–886. doi: 10.1128/aac.27.6.883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pevear D. C., Fancher M. J., Felock P. J., Rossmann M. G., Miller M. S., Diana G., Treasurywala A. M., McKinlay M. A., Dutko F. J. Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors. J Virol. 1989 May;63(5):2002–2007. doi: 10.1128/jvi.63.5.2002-2007.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rossmann M. G., Arnold E., Erickson J. W., Frankenberger E. A., Griffith J. P., Hecht H. J., Johnson J. E., Kamer G., Luo M., Mosser A. G. Structure of a human common cold virus and functional relationship to other picornaviruses. Nature. 1985 Sep 12;317(6033):145–153. doi: 10.1038/317145a0. [DOI] [PubMed] [Google Scholar]
  29. Rozhon E. J., Lipton H. L., Brown F. Characterization of Theiler's murine encephalomyelitis virus RNA. J Gen Virol. 1982 Aug;61(Pt 2):157–165. doi: 10.1099/0022-1317-61-2-157. [DOI] [PubMed] [Google Scholar]
  30. Rozhon E., Cox S., Buontempo P., O'Connell J., Slater W., De Martino J., Schwartz J., Miller G., Arnold E., Zhang A. SCH 38057: a picornavirus capsid-binding molecule with antiviral activity after the initial stage of viral uncoating. Antiviral Res. 1993 May;21(1):15–35. doi: 10.1016/0166-3542(93)90064-p. [DOI] [PubMed] [Google Scholar]
  31. Rueckert R. R., Pallansch M. A. Preparation and characterization of encephalomyocarditis (EMC) virus. Methods Enzymol. 1981;78(Pt A):315–325. [PubMed] [Google Scholar]
  32. Staunton D. E., Merluzzi V. J., Rothlein R., Barton R., Marlin S. D., Springer T. A. A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses. Cell. 1989 Mar 10;56(5):849–853. doi: 10.1016/0092-8674(89)90689-2. [DOI] [PubMed] [Google Scholar]
  33. Strikas R. A., Anderson L. J., Parker R. A. Temporal and geographic patterns of isolates of nonpolio enterovirus in the United States, 1970-1983. J Infect Dis. 1986 Feb;153(2):346–351. doi: 10.1093/infdis/153.2.346. [DOI] [PubMed] [Google Scholar]
  34. Tomassini J. E., Graham D., DeWitt C. M., Lineberger D. W., Rodkey J. A., Colonno R. J. cDNA cloning reveals that the major group rhinovirus receptor on HeLa cells is intercellular adhesion molecule 1. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4907–4911. doi: 10.1073/pnas.86.13.4907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Trousdale M. D., Paque R. E., Gauntt C. J. Isolation of Coxsackievirus B3 temperture-sensitive mutants and their assignment to complementation groups. Biochem Biophys Res Commun. 1976 May 23;76(2):368–375. doi: 10.1016/0006-291x(77)90734-3. [DOI] [PubMed] [Google Scholar]
  36. Turner R. B., Dutko F. J., Goldstein N. H., Lockwood G., Hayden F. G. Efficacy of oral WIN 54954 for prophylaxis of experimental rhinovirus infection. Antimicrob Agents Chemother. 1993 Feb;37(2):297–300. doi: 10.1128/aac.37.2.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Woods M. G., Diana G. D., Rogge M. C., Otto M. J., Dutko F. J., McKinlay M. A. In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug. Antimicrob Agents Chemother. 1989 Dec;33(12):2069–2074. doi: 10.1128/aac.33.12.2069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Yin-Murphy M. Acute hemorrhagic conjunctivitis. Prog Med Virol. 1984;29:23–44. [PubMed] [Google Scholar]
  39. Zhang A., Nanni R. G., Li T., Arnold G. F., Oren D. A., Jacobo-Molina A., Williams R. L., Kamer G., Rubenstein D. A., Li Y. Structure determination of antiviral compound SCH 38057 complexed with human rhinovirus 14. J Mol Biol. 1993 Apr 5;230(3):857–867. doi: 10.1006/jmbi.1993.1206. [DOI] [PubMed] [Google Scholar]
  40. al-Nakib W., Higgins P. G., Barrow G. I., Tyrrell D. A., Andries K., Vanden Bussche G., Taylor N., Janssen P. A. Suppression of colds in human volunteers challenged with rhinovirus by a new synthetic drug (R61837). Antimicrob Agents Chemother. 1989 Apr;33(4):522–525. doi: 10.1128/aac.33.4.522. [DOI] [PMC free article] [PubMed] [Google Scholar]

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