Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication.

Abstract

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 IIV-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 34 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 ict 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.The reverse transcriptase (RT) encoded by human immunodeficiency virus type 1 (HIV-1) catalyzes the conversion of the viral genomic RNA into proviral DNA (1, 2). Since RT is essential for virus replication and has no closely related identified cellular homolog, it has been the prime target for antiviral therapy against theacquired immunodeficiency syndrome (AIDS; refs. 3 and 4). This strategy is appropriate since 3'-azido-2',3'-dideoxythymidine (AZT), a nucleoside analog inhibitor of reverse transcription, was the first drug shown to benefit HIV-1-infected individuals (5). Other nucleoside analog RT inhibitors also show promise in clinical evaluations (6, 7). However, the administration of these drugs to patients is usually limited by serious toxicities (7,8). In addition, HIV-1 with reduced AZT-sensitivity has been obtained from AZT-treated patients, suggesting the emergence of resistant virus will limit the drug's efficacy (9, 10). Thus, effective prolonged treatment of HIV-1 infection likely requires the discovery of other, perhaps multiple, RT inhibitors. To this end, we and others (11, 12) have sought to identify other nonnucleoside HIV-1 RT inhibitors. MATERIALS AND METHODSCell Culture and Virus Infections. The cell cultures were maintained at 370C in 5% C02/95% air. The HIV-1 infectivity studies were conducted in MT-2 cells, peripheral blood mononuclear cells (PBMC), and H9 cells as described (9,(13)(14)(15). In brief, MT-2 or H9 cells were infected with HIV-1 (IlIb isolate) at a multiplicity of infection of 0.001. In MT-2 cells syncytium formation was determined 4 days after infection at the peak of the viral cytopathic effect (13). In H9 cells, growth medium with fresh drug was replaced every 3-4 days, and at 14 days-...

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

“…In contrast to the classical RT inhibitors such as phosphonoformic acid (PFA) and 3'-azido-3'-deoxythymidine (AZT) 5'-triphosphate, TIBO and HEPT inhibit HIV-1 RT, but not HIV-2 RT. The more recently developed dipyridodiazepinones, pyridinones and bis(hetero-aryl)piperazines share this property (Merluzzi et al, 1990;Goldman et al, 1991;Romero et al, 1991). The HIV-l-specific RT inhibitors are ineffective not only against HIV-2 RT, but also against the RTs of avian myeloblastosis virus, Moloney murine leukaemia virus, SIV [from macaques (SlVmac)] and feline leukaemia virus (Merluzzi et al, 1990;Debyser et al, 1991;Goldman et al, 1991).…”

Mechanism of resistance to U‐90152S and sensitization to L‐697,661 by a proline to leucine change at residue 236 of human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase

“…Recently, several classes of nonnucleoside reverse transcriptase inhibitors (NNRTIs), which are also potent inhibitors of HIV-1 replication in cell culture, have been identified. These include the pyridinone L-697,661 [1], nevirapine [2,3], the TIBO derivatives [4], TSAO [5], HEPT [6], inophyllums [7], and the BHAPs [8,9]. Despite their structural dissimilarity, they are all relatively inactive against HIV-2 RT and, in general, are non-competitive with respect to substrates.…”

Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

“…I), all of the drugs are highly specific for HIV-I; i.e., they do not inhibit a variety of other DNA polymerases including HIV-RT type 2. Although most of the drugs (such as nevirapine and the TlBO derivatives) appear to be mechanistically noncompetitive for primer, template, and nucleotide (Kopp et al, 1991;Romero et al, 1991), at least one inhibitor (HEPT) has been reported to be competitive with respect to the natural substrate dTTP (Baba et al, 1991). In addition, nonnucleoside inhibitors show a lower cellular toxicity than nucleoside inhibitors (Pauwels et al, 1990; Romero et al, 1991).…”