Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1992 May;36(5):926–933. doi: 10.1128/aac.36.5.926

In vitro inhibition of human immunodeficiency virus (HIV) type 1 replication by C2 symmetry-based HIV protease inhibitors as single agents or in combinations.

S Kageyama 1, J N Weinstein 1, T Shirasaka 1, D J Kempf 1, D W Norbeck 1, J J Plattner 1, J Erickson 1, H Mitsuya 1
PMCID: PMC188763  PMID: 1510415

Abstract

C2 symmetry-based human immunodeficiency virus (HIV) protease inhibitors were examined in vitro as single agents or in combination with 3'-azido-2',3'-dideoxythymidine (AZT) or 2',3'-dideoxyinosine for activity against HIV type 1 (HIV-1). Ten C2 symmetry-based or pseudo-C2 symmetry-based HIV protease inhibitors were active against a laboratory strain (HIV-1IIIB) in the HIV-1 cytopathic effect inhibition assay. Three inhibitors, A75925, A76928, and A77003, selected to represent a range of aqueous solubility and antiviral activity, were active against four different HIV-1 strains tested. These three inhibitors exhibited a significant inhibition of the cytopathic effect of HIV-1 against the CD4+ ATH8 cell line, with 90% inhibitory concentrations ranging from 0.1 to 4 microM. Cellular toxicity was negligible at up to 20 microM. Furthermore, they completely inhibited the replication of monocytotropic strain HIV-1Ba-L in purified monocytes and macrophages at 0.75 to 2 microM. Potent inhibitory activity against a primary HIV-1 isolate and an AZT-resistant HIV-1 variant was also observed for all three inhibitors in phytohemagglutinin-activated peripheral blood mononuclear cells. When these three HIV protease inhibitors and AZT or 2',3'-dideoxyinosine were used in combinations against a primary HIV isolate in phytohemagglutinin-activated peripheral blood mononuclear cells and the results were analyzed with the COMBO program package, their antiviral activities were identified to be synergistic in some cases and additive in others. The present data warrant further investigations of these compounds as potential antiviral agents for the therapy of HIV infections.

Full text

PDF
926

Images in this article

930Image
on p.930

Selected References

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

  1. Ashorn P., McQuade T. J., Thaisrivongs S., Tomasselli A. G., Tarpley W. G., Moss B. An inhibitor of the protease blocks maturation of human and simian immunodeficiency viruses and spread of infection. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7472–7476. doi: 10.1073/pnas.87.19.7472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ashorn P., Moss B., Weinstein J. N., Chaudhary V. K., FitzGerald D. J., Pastan I., Berger E. A. Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8889–8893. doi: 10.1073/pnas.87.22.8889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cooley T. P., Kunches L. M., Saunders C. A., Ritter J. K., Perkins C. J., McLaren C., McCaffrey R. P., Liebman H. A. Once-daily administration of 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a Phase I trial. N Engl J Med. 1990 May 10;322(19):1340–1345. doi: 10.1056/NEJM199005103221902. [DOI] [PubMed] [Google Scholar]
  4. Daar E. S., Li X. L., Moudgil T., Ho D. D. High concentrations of recombinant soluble CD4 are required to neutralize primary human immunodeficiency virus type 1 isolates. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6574–6578. doi: 10.1073/pnas.87.17.6574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Erickson J., Neidhart D. J., VanDrie J., Kempf D. J., Wang X. C., Norbeck D. W., Plattner J. J., Rittenhouse J. W., Turon M., Wideburg N. Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science. 1990 Aug 3;249(4968):527–533. doi: 10.1126/science.2200122. [DOI] [PubMed] [Google Scholar]
  6. Fischl M. A., Parker C. B., Pettinelli C., Wulfsohn M., Hirsch M. S., Collier A. C., Antoniskis D., Ho M., Richman D. D., Fuchs E. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group. N Engl J Med. 1990 Oct 11;323(15):1009–1014. doi: 10.1056/NEJM199010113231501. [DOI] [PubMed] [Google Scholar]
  7. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  8. Kempf D. J., Marsh K. C., Paul D. A., Knigge M. F., Norbeck D. W., Kohlbrenner W. E., Codacovi L., Vasavanonda S., Bryant P., Wang X. C. Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother. 1991 Nov;35(11):2209–2214. doi: 10.1128/aac.35.11.2209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kempf D. J., Norbeck D. W., Codacovi L., Wang X. C., Kohlbrenner W. E., Wideburg N. E., Paul D. A., Knigge M. F., Vasavanonda S., Craig-Kennard A. Structure-based, C2 symmetric inhibitors of HIV protease. J Med Chem. 1990 Oct;33(10):2687–2689. doi: 10.1021/jm00172a002. [DOI] [PubMed] [Google Scholar]
  10. Kohl N. E., Emini E. A., Schleif W. A., Davis L. J., Heimbach J. C., Dixon R. A., Scolnick E. M., Sigal I. S. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4686–4690. doi: 10.1073/pnas.85.13.4686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kramer R. A., Schaber M. D., Skalka A. M., Ganguly K., Wong-Staal F., Reddy E. P. HTLV-III gag protein is processed in yeast cells by the virus pol-protease. Science. 1986 Mar 28;231(4745):1580–1584. doi: 10.1126/science.2420008. [DOI] [PubMed] [Google Scholar]
  12. Lambert J. S., Seidlin M., Reichman R. C., Plank C. S., Laverty M., Morse G. D., Knupp C., McLaren C., Pettinelli C., Valentine F. T. 2',3'-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. N Engl J Med. 1990 May 10;322(19):1333–1340. doi: 10.1056/NEJM199005103221901. [DOI] [PubMed] [Google Scholar]
  13. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  14. McQuade T. J., Tomasselli A. G., Liu L., Karacostas V., Moss B., Sawyer T. K., Heinrikson R. L., Tarpley W. G. A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation. Science. 1990 Jan 26;247(4941):454–456. doi: 10.1126/science.2405486. [DOI] [PubMed] [Google Scholar]
  15. Meek T. D., Lambert D. M., Dreyer G. B., Carr T. J., Tomaszek T. A., Jr, Moore M. L., Strickler J. E., Debouck C., Hyland L. J., Matthews T. J. Inhibition of HIV-1 protease in infected T-lymphocytes by synthetic peptide analogues. Nature. 1990 Jan 4;343(6253):90–92. doi: 10.1038/343090a0. [DOI] [PubMed] [Google Scholar]
  16. Merigan T. C., Skowron G., Bozzette S. A., Richman D., Uttamchandani R., Fischl M., Schooley R., Hirsch M., Soo W., Pettinelli C. Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. A phase I and II study. Ann Intern Med. 1989 Feb 1;110(3):189–194. doi: 10.7326/0003-4819-110-3-189. [DOI] [PubMed] [Google Scholar]
  17. Mitsuya H., Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1911–1915. doi: 10.1073/pnas.83.6.1911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mitsuya H., Weinhold K. J., Furman P. A., St Clair M. H., Lehrman S. N., Gallo R. C., Bolognesi D., Barry D. W., Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mitsuya H., Yarchoan R., Broder S. Molecular targets for AIDS therapy. Science. 1990 Sep 28;249(4976):1533–1544. doi: 10.1126/science.1699273. [DOI] [PubMed] [Google Scholar]
  20. Mitsuya H., Yarchoan R., Kageyama S., Broder S. Targeted therapy of human immunodeficiency virus-related disease. FASEB J. 1991 Jul;5(10):2369–2381. doi: 10.1096/fasebj.5.10.1712326. [DOI] [PubMed] [Google Scholar]
  21. Popovic M., Sarngadharan M. G., Read E., Gallo R. C. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984 May 4;224(4648):497–500. doi: 10.1126/science.6200935. [DOI] [PubMed] [Google Scholar]
  22. Rooke R., Tremblay M., Soudeyns H., DeStephano L., Yao X. J., Fanning M., Montaner J. S., O'Shaughnessy M., Gelmon K., Tsoukas C. Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group. AIDS. 1989 Jul;3(7):411–415. doi: 10.1097/00002030-198907000-00001. [DOI] [PubMed] [Google Scholar]
  23. Shirasaka T., Murakami K., Ford H., Jr, Kelley J. A., Yoshioka H., Kojima E., Aoki S., Broder S., Mitsuya H. Lipophilic halogenated congeners of 2',3'-dideoxypurine nucleosides active against human immunodeficiency virus in vitro. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9426–9430. doi: 10.1073/pnas.87.23.9426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Vacca J. P., Guare J. P., deSolms S. J., Sanders W. M., Giuliani E. A., Young S. D., Darke P. L., Zugay J., Sigal I. S., Schleif W. A. L-687,908, a potent hydroxyethylene-containing HIV protease inhibitor. J Med Chem. 1991 Mar;34(3):1225–1228. doi: 10.1021/jm00107a050. [DOI] [PubMed] [Google Scholar]
  25. Weinstein J. N., Bunow B., Weislow O. S., Schinazi R. F., Wahl S. M., Wahl L. M., Szebeni J. Synergistic drug combinations in AIDS therapy. Dipyridamole/3'-azido-3'-deoxythymidine in particular and principles of analysis in general. Ann N Y Acad Sci. 1990;616:367–384. doi: 10.1111/j.1749-6632.1990.tb17857.x. [DOI] [PubMed] [Google Scholar]
  26. Yarchoan R., Mitsuya H., Broder S. Strategies for the combination therapy of HIV infection. J Acquir Immune Defic Syndr. 1990;3 (Suppl 2):S99–103. [PubMed] [Google Scholar]
  27. Yarchoan R., Mitsuya H., Thomas R. V., Pluda J. M., Hartman N. R., Perno C. F., Marczyk K. S., Allain J. P., Johns D. G., Broder S. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science. 1989 Jul 28;245(4916):412–415. doi: 10.1126/science.2502840. [DOI] [PubMed] [Google Scholar]
  28. Yarchoan R., Perno C. F., Thomas R. V., Klecker R. W., Allain J. P., Wills R. J., McAtee N., Fischl M. A., Dubinsky R., McNeely M. C. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet. 1988 Jan 16;1(8577):76–81. doi: 10.1016/s0140-6736(88)90283-8. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES