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

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.

Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase

“…In contrast, AZT was effective against all of these viruses, confirming previous reports (23,35,45,47,53).…”

Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms

“…The importance of the choice of the template used to assess the ability of a compound to inhibit RT has also been demonstrated for diverse, nonnucleoside, HIV-1-specific RT inhibitors (7,22,24,25). As with michellamine B, compounds of that general class showed the greatest inhibition of RT activity when a heteropolymer RNA template was used.…”

Cell-Based and Biochemical Analysis of the anti-HIV Activity of Combinations of 3′-azido-3′-deoxythymidine and Analogues of TIBO

“…The specificity of the TIBO analogues for HIV-1 appears to resultfrom the tertiary structure ofthe HIV-1 RT molecule (Shih et aI., 1991;Condra et al, 1992) and binding of the agents to the enzyme may only occur after unfolding of the binding region. Other non-nucleoside inhibitors of HIV-1 reverse transcription described apparently bind in the same pocket of HIV-1 reverse transcriptase and have an antiviral spectrum similar to the TIBO compounds (Merluzzi et al, 1990;Goldman et aI., 1991;Romero et al, 1991;Camarasa et aI., 1992;Klunder et aI., 1992;Buckheit et aI., 1993;McMahon et al, 1993). However, this class of compounds has been found to rapidly select for the replication of drug-resistant virus isolates in cell culture (Nunberg et al, 1991;Richman et al, 1991a;Mellors et al, 1992).…”