Nonnucleoside Reverse Transcriptase Inhibitors that Potently and Specifically Block Human Immunodeficiency Virus Type 1 Replication

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 88; no. 19; pp. 8806 - 8810
• Main Authors: Romero, D. L., Busso, M., C.-K. Tan, Reusser, F., Palmer, J. R., Poppe, S. M., Aristoff, P. A., Downey, K. M., So, A. G., Resnick, L., Tarpley, W. G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01-10-1991; National Acad Sciences
• Subjects: Animals; Antiviral Agents; Antivirals; Cell Survival - drug effects; Dideoxynucleotides; DNA; DNA, Viral - analysis; Drug Synergism; HIV; HIV 1; HIV-1 - drug effects; HIV-1 - growth & development; human immunodeficiency virus 1; Infections; Inhibitory concentration 50; Lymphocytes; Mice; Mice, Nude; Piperazines - pharmacology; Polymerase Chain Reaction; Reverse Transcriptase Inhibitors; RNA; RNA, Viral - analysis; Thymine Nucleotides - pharmacology; Virus Replication - drug effects; Viruses; Zidovudine - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.19.8806

Certain bis(heteroaryl)piperazines (BHAPs) are potent inhibitors of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) at concentrations lower by 2-4 orders of magnitude than that which inhibits normal cellular DNA polymerase activity. Combination of a BHAP with nucleoside analog HIV-1 RT inhibitors suggested that together these compounds inhibited RT synergistically. In three human lymphocytic cell systems using several laboratory and clinical HIV-1 isolates, the BHAPs blocked HIV-1 replication with potencies nearly identical to those of 3'-azido-2', 3'-dideoxythymidine or 2',3-dideoxyadenosine; in primary cultures of human peripheral blood mononuclear cells, concentrations of these antiviral agents were lower by at least 3-4 orders of magnitude than cytotoxic levels. The BHAPs do not inhibit replication of HIV-2, the simian or feline immunodeficiency virus, or Rauscher murine leukemia virus in culture. Evaluation of a BHAP in HIV-1-infected SCID-hu mice (severe combined immunodeficient mice implanted with human fetal lymph node) showed that the compound could block HIV-1 replication in vivo. The BHAPs are readily obtained synthetically and have been extensively characterized in preclinical evaluations. These compounds hold promise for the treatment of HIV-1 infection.