Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 Apr;37(4):754–760. doi: 10.1128/aac.37.4.754

Diarylsulfones, a new chemical class of nonnucleoside antiviral inhibitors of human immunodeficiency virus type 1 reverse transcriptase.

J B McMahon 1, R J Gulakowski 1, O S Weislow 1, R J Schultz 1, V L Narayanan 1, D J Clanton 1, R Pedemonte 1, F W Wassmundt 1, R W Buckheit Jr 1, W D Decker 1, et al.
PMCID: PMC187752  PMID: 7684215

Abstract

A series of variously substituted diarylsulfones and related derivatives were found to prevent human immunodeficiency virus type 1 (HIV-1) replication and HIV-1-induced cell killing in vitro. One of the more potent derivatives, 2-nitrophenyl phenyl sulfone (NPPS), completely protected human CEM-SS lymphoblastoid cells from the cytopathic effects of HIV-1 in cell culture at 1 to 5 microM concentrations. HIV-1 replication, as assessed by the production of infectious virions, viral p24 antigen, and virion reverse transcriptase (RT), was inhibited by NPPS at similar concentrations. There was no evidence of direct cytotoxicity of the drug at concentrations below 100 microM. A variety of other CD4+ T-cell lines as well as cultures of peripheral blood leukocytes and monocytes were protected from HIV-1-induced cytopathicity and/or viral replication. NPPS also inhibited several distinctly different strains of HIV-1 but was ineffective against three strains of HIV-2. Biochemical studies revealed that NPPS inhibited HIV-1 RT but not HIV-2 RT. NPPS had no direct effect on HIV-1 virions, nor did it block the initial binding of HIV-1 to target cells. Time-limited treatments of cells with NPPS found that NPPS had to be present continuously in culture to provide maximum antiviral protection. In addition, HIV-1 replication in cells in which infection was already fully established or in chronically infected cells was also unaffected by NPPS. We conclude that NPPS acts in a reversible manner as a nonnucleoside HIV-1-specific RT inhibitor. Although markedly different in structure from a larger, structurally diverse group of known HIV-1-specific nonnucleoside RT inhibitors, NPPS shares several of the biological properties that characterize this emerging new pharmacologic class.

Full text

PDF
754

Selected References

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

  1. Cloyd M. W., Moore B. E. Spectrum of biological properties of human immunodeficiency virus (HIV-1) isolates. Virology. 1990 Jan;174(1):103–116. doi: 10.1016/0042-6822(90)90059-z. [DOI] [PubMed] [Google Scholar]
  2. Gulakowski R. J., McMahon J. B., Staley P. G., Moran R. A., Boyd M. R. A semiautomated multiparameter approach for anti-HIV drug screening. J Virol Methods. 1991 Jun;33(1-2):87–100. doi: 10.1016/0166-0934(91)90010-w. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. McCaffrey T. A., Agarwal L. A., Weksler B. B. A rapid fluorometric DNA assay for the measurement of cell density and proliferation in vitro. In Vitro Cell Dev Biol. 1988 Mar;24(3):247–252. doi: 10.1007/BF02623555. [DOI] [PubMed] [Google Scholar]
  5. Nunberg J. H., Schleif W. A., Boots E. J., O'Brien J. A., Quintero J. C., Hoffman J. M., Emini E. A., Goldman M. E. Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors. J Virol. 1991 Sep;65(9):4887–4892. doi: 10.1128/jvi.65.9.4887-4892.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Parker W. B., White E. L., Shaddix S. C., Ross L. J., Buckheit R. W., Jr, Germany J. M., Secrist J. A., 3rd, Vince R., Shannon W. M. Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases alpha, beta, and gamma by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs. J Biol Chem. 1991 Jan 25;266(3):1754–1762. [PubMed] [Google Scholar]
  7. Rink T. J., Tsien R. Y., Pozzan T. Cytoplasmic pH and free Mg2+ in lymphocytes. J Cell Biol. 1982 Oct;95(1):189–196. doi: 10.1083/jcb.95.1.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Saag M. S., Crain M. J., Decker W. D., Campbell-Hill S., Robinson S., Brown W. E., Leuther M., Whitley R. J., Hahn B. H., Shaw G. M. High-level viremia in adults and children infected with human immunodeficiency virus: relation to disease stage and CD4+ lymphocyte levels. J Infect Dis. 1991 Jul;164(1):72–80. doi: 10.1093/infdis/164.1.72. [DOI] [PubMed] [Google Scholar]
  9. Weislow O. S., Kiser R., Fine D. L., Bader J., Shoemaker R. H., Boyd M. R. New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity. J Natl Cancer Inst. 1989 Apr 19;81(8):577–586. doi: 10.1093/jnci/81.8.577. [DOI] [PubMed] [Google Scholar]
  10. White E. L., Buckheit R. W., Jr, Ross L. J., Germany J. M., Andries K., Pauwels R., Janssen P. A., Shannon W. M., Chirigos M. A. A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer templates. Antiviral Res. 1991 Oct;16(3):257–266. doi: 10.1016/0166-3542(91)90005-c. [DOI] [PubMed] [Google Scholar]

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

RESOURCES