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. 1989 Aug;86(15):5963–5967. doi: 10.1073/pnas.86.15.5963

Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin.

G Lavie 1, F Valentine 1, B Levin 1, Y Mazur 1, G Gallo 1, D Lavie 1, D Weiner 1, D Meruelo 1
PMCID: PMC297751  PMID: 2548193

Abstract

Administration of the aromatic polycyclic dione compounds hypericin or pseudohypericin to experimental animals provides protection from disease induced by retroviruses that give rise to acute, as well as slowly progressive, diseases. For example, survival from Friend virus-induced leukemia is significantly prolonged by both compounds, with hypericin showing the greater potency. Viremia induced by LP-BM5 murine immunodeficiency virus is markedly suppressed after infrequent dosage of either substance. These compounds affect the retroviral infection and replication cycle at least at two different points: (i) Assembly or processing of intact virions from infected cells was shown to be affected by hypericin. Electron microscopy of hypericin-treated, virus-producing cells revealed the production of particles containing immature or abnormally assembled cores, suggesting the compounds may interfere with processing of gag-encoded precursor polyproteins. The released virions contain no detectable activity of reverse transcriptase. (ii) Hypericin and pseudohypericin also directly inactivate mature and properly assembled retroviruses as determined by assays for reverse transcriptase and infectivity. Accumulating data from our laboratories suggest that these compounds inhibit retroviruses by unconventional mechanisms and that the potential therapeutic value of hypericin and pseudohypericin should be explored in diseases such as AIDS.

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Selected References

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  1. Bach R. G., Meruelo D. Identification of a 36,000-molecular weight, gag-related phosphoprotein in lymphoma cells transformed by radiation leukemia virus. J Exp Med. 1984 Jul 1;160(1):270–285. doi: 10.1084/jem.160.1.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bister K., Hayman M. J., Vogt P. K. Defectiveness of avian myelocytomatosis virus MC29: isolation of long-term nonproducer cultures and analysis of virus-specific polypeptide synthesis. Virology. 1977 Oct 15;82(2):431–448. doi: 10.1016/0042-6822(77)90017-4. [DOI] [PubMed] [Google Scholar]
  3. Bolognesi D. P., Montelaro R. C., Frank H., Schäfer W. Assembly of type C oncornaviruses: a model. Science. 1978 Jan 13;199(4325):183–186. doi: 10.1126/science.202022. [DOI] [PubMed] [Google Scholar]
  4. Eisenman R. N., Mason W. S., Linial M. Synthesis and processing of polymerase proteins of wild-type and mutant avian retroviruses. J Virol. 1980 Oct;36(1):62–78. doi: 10.1128/jvi.36.1.62-78.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Eisenman R., Vogt V. M., Diggelmann H. Synthesis of avian RNA tumor virus structural proteins. Cold Spring Harb Symp Quant Biol. 1975;39(Pt 2):1067–1075. doi: 10.1101/sqb.1974.039.01.122. [DOI] [PubMed] [Google Scholar]
  6. FRIEND C. Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia. J Exp Med. 1957 Apr 1;105(4):307–318. doi: 10.1084/jem.105.4.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hanafusa H., Baltimore D., Smoler D., Watson K. F., Yaniv A., Spiegelman S. Absence of polymerase protein in virions of alpha-type rous sarcoma virus. Science. 1972 Sep 29;177(4055):1188–1191. doi: 10.1126/science.177.4055.1188. [DOI] [PubMed] [Google Scholar]
  8. Hayman M. J., Royer-Pokora B., Graf T. Defectiveness of avian erythroblastosis virus: synthesis of a 75K gag-related protein. Virology. 1979 Jan 15;92(1):31–45. doi: 10.1016/0042-6822(79)90212-5. [DOI] [PubMed] [Google Scholar]
  9. Katoh I., Yoshinaka Y., Rein A., Shibuya M., Odaka T., Oroszlan S. Murine leukemia virus maturation: protease region required for conversion from "immature" to "mature" core form and for virus infectivity. Virology. 1985 Sep;145(2):280–292. doi: 10.1016/0042-6822(85)90161-8. [DOI] [PubMed] [Google Scholar]
  10. Kawai S., Hanafusa H. Isolation of defective mutant of avian sarcoma virus. Proc Natl Acad Sci U S A. 1973 Dec;70(12):3493–3497. doi: 10.1073/pnas.70.12.3493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Klinken S. P., Fredrickson T. N., Hartley J. W., Yetter R. A., Morse H. C., 3rd Evolution of B cell lineage lymphomas in mice with a retrovirus-induced immunodeficiency syndrome, MAIDS. J Immunol. 1988 Feb 15;140(4):1123–1131. [PubMed] [Google Scholar]
  12. Levin J. G., Grimley P. M., Ramseur J. M., Berezesky I. K. Deficiency of 60 to 70S RNA in murine leukemia virus particles assembled in cells treated with actinomycin D. J Virol. 1974 Jul;14(1):152–161. doi: 10.1128/jvi.14.1.152-161.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Levy J. A., Shimabukuro J. Recovery of AIDS-associated retroviruses from patients with AIDS or AIDS-related conditions and from clinically healthy individuals. J Infect Dis. 1985 Oct;152(4):734–738. doi: 10.1093/infdis/152.4.734. [DOI] [PubMed] [Google Scholar]
  14. Linial M., Fenno J., Burnette W. N., Rohrschneider L. Synthesis and processing of viral glycoproteins in two nonconditional mutants of Rous sarcoma virus. J Virol. 1980 Oct;36(1):280–290. doi: 10.1128/jvi.36.1.280-290.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Linial M., Medeiros E., Hayward W. S. An avian oncovirus mutant (SE 21Q1b) deficient in genomic RNA: biological and biochemical characterization. Cell. 1978 Dec;15(4):1371–1381. doi: 10.1016/0092-8674(78)90062-4. [DOI] [PubMed] [Google Scholar]
  16. Meruelo D., Lavie G., Lavie D. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5230–5234. doi: 10.1073/pnas.85.14.5230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Meruelo D., Lieberman M., Deak B., McDevitt H. O. Genetic control of radiation leukemia virus-induced tumorigenesis II. Influence of Srlv-1, a locus not linked to H-2. J Exp Med. 1977 Oct 1;146(4):1088–1095. doi: 10.1084/jem.146.4.1088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mosier D. E., Yetter R. A., Morse H. C., 3rd Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice. J Exp Med. 1985 Apr 1;161(4):766–784. doi: 10.1084/jem.161.4.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Panet A., Haseltine W. A., Baltimore D., Peters G., Harada F., Dahlberg J. E. Specific binding of tryptophan transfer RNA to avian myeloblastosis virus RNA-dependent DNA polymerase (reverse transcriptase). Proc Natl Acad Sci U S A. 1975 Jul;72(7):2535–2539. doi: 10.1073/pnas.72.7.2535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pinter A., deHarven E. Protein composition of a defective murine sarcoma virus particle possessing the enveloped type-A morphology. Virology. 1979 Nov;99(1):103–110. doi: 10.1016/0042-6822(79)90041-2. [DOI] [PubMed] [Google Scholar]
  21. Ramsay G., Hayman M. J. Analysis of cells transformed by defective leukemia virus OK10: production of noninfectious particles and synthesis of Pr76gag and an additional 200,000-dalton protein. Virology. 1980 Oct 15;106(1):71–81. doi: 10.1016/0042-6822(80)90222-6. [DOI] [PubMed] [Google Scholar]
  22. Ramsay G., Hayman M. J. Analysis of cells transformed by defective leukemia virus OK10: production of noninfectious particles and synthesis of Pr76gag and an additional 200,000-dalton protein. Virology. 1980 Oct 15;106(1):71–81. doi: 10.1016/0042-6822(80)90222-6. [DOI] [PubMed] [Google Scholar]
  23. Scheele C. M., Hanafusa H. Proteins of helper-dependent RSV. Virology. 1971 Aug;45(2):401–410. doi: 10.1016/0042-6822(71)90341-2. [DOI] [PubMed] [Google Scholar]
  24. Steeves R. A., Eckner R. J., Bennett M., Mirand E. A., Trudel P. J. Isolation and characterization of a lymphatic leukemia virus in the Friend virus complex. J Natl Cancer Inst. 1971 Jun;46(6):1209–1217. [PubMed] [Google Scholar]
  25. Troxler D. H., Scolnick E. M. Rapid leukemia induced by cloned friend strain of replicating murine type-C virus. Association with induction of xenotropic-related RNA sequences contained in spleen focus-forming virus. Virology. 1978 Mar;85(1):17–27. doi: 10.1016/0042-6822(78)90408-7. [DOI] [PubMed] [Google Scholar]
  26. Yoshinaka Y., Ishigame K., Ohno T., Kageyama S., Shibata K., Luftig R. B. Preparations enriched for "immature" murine leukemia virus particles that remain in tissue culture fluids are deficient in Pr65gag proteolyic activity. Virology. 1980 Jan 15;100(1):130–140. doi: 10.1016/0042-6822(80)90559-0. [DOI] [PubMed] [Google Scholar]
  27. Yoshinaka Y., Luftig R. B. Murine leukemia virus morphogenesis: cleavage of P70 in vitro can be accompanied by a shift from a concentrically coiled internal strand ("immature") to a collapsed ("mature") form of the virus core. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3446–3450. doi: 10.1073/pnas.74.8.3446. [DOI] [PMC free article] [PubMed] [Google Scholar]

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