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. 1988 Dec;82(6):2011–2016. doi: 10.1172/JCI113821

Protease inhibitors suppress the in vitro and in vivo replication of rotavirus.

S L Vonderfecht 1, R L Miskuff 1, S B Wee 1, S Sato 1, R R Tidwell 1, J D Geratz 1, R H Yolken 1
PMCID: PMC442783  PMID: 2848866

Abstract

Rotaviruses are major causes of infectious gastroenteritis in humans and other animals. We found that a variety of protease inhibitors suppressed the replication of the SA-11 strain of rotavirus in MA-104 cell cultures. Three of these compounds, leupeptin, pentamidine, and bis (5-amidino-2-benzimidazolyl) methane (BABIM) also restricted the intestinal replication of the murine strain of rotavirus when protease inhibitor and virus were administered simultaneously to suckling mice. Repeated administration of BABIM resulted in significantly reduced levels of intestinal rotaviral antigen even if administration of the compound was begun as late as 48 h after viral inoculation. Additionally, BABIM-treated animals had significantly less intestinal replication of rotavirus than did placebo-treated controls when placed in a heavily rotavirus-contaminated environment. The use of protease inhibitors represents a novel approach to the control of this important gastrointestinal pathogen and is a potential modality for the prevention and treatment of diseases caused by other enteric viruses, for which proteolytic cleavage is necessary for efficient replication.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen K. B. Leupeptin inhibits retrovirus infection in mouse fibroblasts. J Virol. 1983 Dec;48(3):765–769. doi: 10.1128/jvi.48.3.765-769.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Appleyard G., Tisdale M. Inhibition of the growth of human coronavirus 229E by leupeptin. J Gen Virol. 1985 Feb;66(Pt 2):363–366. doi: 10.1099/0022-1317-66-2-363. [DOI] [PubMed] [Google Scholar]
  3. Babiuk L. A., Mohammed K., Spence L., Fauvel M., Petro R. Rotavirus isolation and cultivation in the presence of trypsin. J Clin Microbiol. 1977 Dec;6(6):610–617. doi: 10.1128/jcm.6.6.610-617.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown R. E., Katz M. Failure of antibody production to yellow fever vaccine in children with kwashiorkor. Trop Geogr Med. 1966 Jun;18(2):125–128. [PubMed] [Google Scholar]
  5. Clark S. M., Roth J. R., Clark M. L., Barnett B. B., Spendlove R. S. Trypsin enhancement of rotavirus infectivity: mechanism of enhancement. J Virol. 1981 Sep;39(3):816–822. doi: 10.1128/jvi.39.3.816-822.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cukor G., Blacklow N. R., Capozza F. E., Panjvani Z. F., Bednarek F. Persistence of antibodies to rotavirus in human milk. J Clin Microbiol. 1979 Jan;9(1):93–96. doi: 10.1128/jcm.9.1.93-96.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dubovi E. J., Geratz J. D., Shaver S. R., Tidwell R. R. Inhibition of respiratory syncytial virus-host cell interactions by mono- and diamidines. Antimicrob Agents Chemother. 1981 Apr;19(4):649–656. doi: 10.1128/aac.19.4.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dubovi E. J., Geratz J. D., Tidwell R. R. Inhibition of respiratory syncytial virus by bis(5-amidino-2-benzimidazolyl)methane. Virology. 1980 Jun;103(2):502–509. doi: 10.1016/0042-6822(80)90207-x. [DOI] [PubMed] [Google Scholar]
  9. Estes M. K., Graham D. Y., Mason B. B. Proteolytic enhancement of rotavirus infectivity: molecular mechanisms. J Virol. 1981 Sep;39(3):879–888. doi: 10.1128/jvi.39.3.879-888.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Estes M. K., Palmer E. L., Obijeski J. F. Rotaviruses: a review. Curr Top Microbiol Immunol. 1983;105:123–184. doi: 10.1007/978-3-642-69159-1_3. [DOI] [PubMed] [Google Scholar]
  11. Eydelloth R. S., Vonderfecht S. L., Sheridan J. F., Enders L. D., Yolken R. H. Kinetics of viral replication and local and systemic immune responses in experimental rotavirus infection. J Virol. 1984 Jun;50(3):947–950. doi: 10.1128/jvi.50.3.947-950.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Flewett T. H., Woode G. N. The rotaviruses. Arch Virol. 1978;57(1):1–23. doi: 10.1007/BF01315633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Geratz J. D., Whitmore A. C. Diamidino-alpha,omega-diphenoxyalkanes. Structure-activity relationships for the inhibition of thrombin, pancreatic kallikrein, and trypsin. J Med Chem. 1973 Sep;16(9):970–975. doi: 10.1021/jm00267a003. [DOI] [PubMed] [Google Scholar]
  14. Ichihashi Y., Oie M. Proteolytic activation of vaccinia virus for the penetration phase of infection. Virology. 1982 Jan 15;116(1):297–305. doi: 10.1016/0042-6822(82)90421-4. [DOI] [PubMed] [Google Scholar]
  15. John T. J., Christopher S. Oral polio vaccination of children in the tropics. III. Intercurrent enterovirus infections, vaccine virus take and antibody response. Am J Epidemiol. 1975 Nov;102(5):422–428. doi: 10.1093/oxfordjournals.aje.a112181. [DOI] [PubMed] [Google Scholar]
  16. Kapikian A. Z., Kim H. W., Wyatt R. G., Cline W. L., Arrobio J. O., Brandt C. D., Rodriguez W. J., Sack D. A., Chanock R. M., Parrott R. H. Human reovirus-like agent as the major pathogen associated with "winter" gastroenteritis in hospitalized infants and young children. N Engl J Med. 1976 Apr 29;294(18):965–972. doi: 10.1056/NEJM197604292941801. [DOI] [PubMed] [Google Scholar]
  17. Kaplan J. E., Schonberger L. B., Varano G., Jackman N., Bied J., Gary G. W. An outbreak of acute nonbacterial gastroenteritis in a nursing home. Demonstration of person-to-person transmission by temporal clustering of cases. Am J Epidemiol. 1982 Dec;116(6):940–948. doi: 10.1093/oxfordjournals.aje.a113496. [DOI] [PubMed] [Google Scholar]
  18. Keswick B. H., Blacklow N. R., Cukor G. C., DuPont H. L., Vollet J. L. Norwalk virus and rotavirus in travellers' diarrhoea in Mexico. Lancet. 1982 Jan 9;1(8263):109–110. doi: 10.1016/s0140-6736(82)90247-1. [DOI] [PubMed] [Google Scholar]
  19. Kim H. W., Brandt C. D., Kapikian A. Z., Wyatt R. G., Arrobio J. O., Rodriguez W. J., Chanock R. M., Parrott R. H. Human reovirus-like agent infection. Occurrence in adult contacts of pediatric patients with gastroenteritis. JAMA. 1977 Aug 1;238(5):404–407. doi: 10.1001/jama.238.5.404. [DOI] [PubMed] [Google Scholar]
  20. Losonsky G. A., Johnson J. P., Winkelstein J. A., Yolken R. H. Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis. A pharmacokinetic and functional analysis. J Clin Invest. 1985 Dec;76(6):2362–2367. doi: 10.1172/JCI112248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marrie T. J., Lee S. H., Faulkner R. S., Ethier J., Young C. H. Rotavirus infection in a geriatric population. Arch Intern Med. 1982 Feb;142(2):313–316. [PubMed] [Google Scholar]
  22. Mata L. J., Wyatt R. G. The uniqueness of human milk. Host resistance to infection. Am J Clin Nutr. 1971 Aug;24(8):976–986. doi: 10.1093/ajcn/24.8.976. [DOI] [PubMed] [Google Scholar]
  23. Muramatsu M., Homma M. Trypsin action on the growth of Sendai virus in tissue culture cells. V. An activating enzyme for Sendai virus in the chorioallantoic fluid of the embryonated chicken egg. Microbiol Immunol. 1980;24(2):113–122. doi: 10.1111/j.1348-0421.1980.tb00569.x. [DOI] [PubMed] [Google Scholar]
  24. ROSEN F. S., JANEWAY C. A. DANGERS OF VACCINATION IN LYMPHOPENIC INFANTS. Pediatrics. 1964 Feb;33:310–311. [PubMed] [Google Scholar]
  25. Saulsbury F. T., Winkelstein J. A., Yolken R. H. Chronic rotavirus infection in immunodeficiency. J Pediatr. 1980 Jul;97(1):61–65. doi: 10.1016/s0022-3476(80)80131-4. [DOI] [PubMed] [Google Scholar]
  26. Sheridan J. F., Eydelloth R. S., Vonderfecht S. L., Aurelian L. Virus-specific immunity in neonatal and adult mouse rotavirus infection. Infect Immun. 1983 Feb;39(2):917–927. doi: 10.1128/iai.39.2.917-927.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Steel R. B., Torres-Medina A. Effects of environmental and dietary factors on human rotavirus infection in gnotobiotic piglets. Infect Immun. 1984 Mar;43(3):906–911. doi: 10.1128/iai.43.3.906-911.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Theil K. W., Bohl E. H. Porcine rotaviral infection of cell culture: effects of certain enzymes. Am J Vet Res. 1980 Jan;41(1):140–143. [PubMed] [Google Scholar]
  29. Tidwell R. R., Geratz J. D., Clyde W. A., Jr, Rosenthal K. U., Dubovi E. J. Suppression of respiratory syncytial virus infection in cotton rats by bis(5-amidino-2-benzimidazolyl)methane. Antimicrob Agents Chemother. 1984 Oct;26(4):591–593. doi: 10.1128/aac.26.4.591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tidwell R. R., Geratz J. D., Dann O., Volz G., Zeh D., Loewe H. Diarylamidine derivatives with one or both of the aryl moieties consisting of an indole or indole-like ring. Inhibitors of arginine-specific esteroproteases. J Med Chem. 1978 Jul;21(7):613–623. doi: 10.1021/jm00205a005. [DOI] [PubMed] [Google Scholar]
  31. Urasawa T., Urasawa S., Taniguchi K. Sequential passages of human rotavirus in MA-104 cells. Microbiol Immunol. 1981;25(10):1025–1035. doi: 10.1111/j.1348-0421.1981.tb00109.x. [DOI] [PubMed] [Google Scholar]
  32. Vesikari T., Isolauri E., D'Hondt E., Delem A., André F. E., Zissis G. Protection of infants against rotavirus diarrhoea by RIT 4237 attenuated bovine rotavirus strain vaccine. Lancet. 1984 May 5;1(8384):977–981. doi: 10.1016/s0140-6736(84)92323-7. [DOI] [PubMed] [Google Scholar]
  33. Vollet J. J., Ericsson C. D., Gibson G., Pickering L. K., DuPont H. L., Kohl S., Conklin R. H. Human rotavirus in an adult population with travelers' diarrhea and its relationship to the location of food consumption. J Med Virol. 1979;4(2):81–87. doi: 10.1002/jmv.1890040202. [DOI] [PubMed] [Google Scholar]
  34. Vonderfecht S. L., Huber A. C., Eiden J., Mader L. C., Yolken R. H. Infectious diarrhea of infant rats produced by a rotavirus-like agent. J Virol. 1984 Oct;52(1):94–98. doi: 10.1128/jvi.52.1.94-98.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yolken R. H., Bishop C. A., Townsend T. R., Bolyard E. A., Bartlett J., Santos G. W., Saral R. Infectious gastroenteritis in bone-marrow-transplant recipients. N Engl J Med. 1982 Apr 29;306(17):1010–1012. doi: 10.1056/NEJM198204293061701. [DOI] [PubMed] [Google Scholar]
  36. Yolken R. H., Wyatt R. G., Mata L., Urrutia J. J., Garciá B., Chanock R. M., Kapikian A. Z. Secretory antibody directed against rotavirus in human milk--measurement by means of enzyme-linked immunosorbent assay. J Pediatr. 1978 Dec;93(6):916–921. doi: 10.1016/s0022-3476(78)81211-6. [DOI] [PubMed] [Google Scholar]
  37. Zhirnov O. P., Ovcharenko A. V., Bukrinskaya A. G. Suppression of influenza virus replication in infected mice by protease inhibitors. J Gen Virol. 1984 Jan;65(Pt 1):191–196. doi: 10.1099/0022-1317-65-1-191. [DOI] [PubMed] [Google Scholar]
  38. von Bonsdorff C. H., Hovi T., Mäkelä P., Mörttinen A. Rotavirus infections in adults in association with acute gastroenteritis. J Med Virol. 1978;2(1):21–28. doi: 10.1002/jmv.1890020105. [DOI] [PubMed] [Google Scholar]

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