A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides

Herrewege, Yven Van; Vanham, Guido; Michiels, Jo; Fransen, Katrien; Kestens, Luc; Andries, Koen; Janßen, Paul; Lewi, Paul

doi:10.1128/aac.48.10.3684-3689.2004

Cited by 56 publications

(33 citation statements)

References 28 publications

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“…Probably its requirement for three phosphorylation steps to obtain its bioactive form impaired its efficiency in our infection model of nonactivated primary target cells (10). Consistent with the findings in previous reports, the NtRTI and NNRTIs potently blocked HIV-1 infection, regardless of the dose and source of virus (17,51,57,59). Interestingly, both L-870812 and PMPA showed similar prevention capacities against infections driven by either cell-free virus or cell-associated virus.…”

supporting

confidence: 79%

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Terrazas-Aranda

Herrewege

Hazuda

et al. 2008

Antimicrob Agents Chemother

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Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4؉ T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for microbicide development.

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supporting

confidence: 79%

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Terrazas-Aranda

Herrewege

Hazuda

et al. 2008

Antimicrob Agents Chemother

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“…Stimulated CD4 ϩ T lymphocytes were incubated with fluorochrome-conjugated NB325 for 1 h at 37°C. TMC120 and UC781 (2,15,17,21,22) is likely a consequence of compound penetration of the host cell membrane (15) and intracellular inhibition of reverse transcription (10,15). Alternatively, these compounds may penetrate the envelopes of cell-free virions by the same mechanism and inhibit the reverse transcriptase molecules packaged in the virion even before the virus has attached to and entered the cell (2,17).…”

Section: Fig 6 Nb325 Binds Persistently To Cd4mentioning

confidence: 99%

Persistent Interactions between Biguanide-Based Compound NB325 and CXCR4 Result in Prolonged Inhibition of Human Immunodeficiency Virus Type 1 Infection

Thakkar

Pirrone

Passic

et al. 2010

Antimicrob Agents Chemother

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We previously demonstrated that the biguanide-based compound NB325 inhibits human immunodeficiency virus type 1 (HIV-1) infection by interacting with the CXCR4 viral coreceptor. This interaction also appeared to be persistent, since HIV-1 infection was inhibited even when the virus was introduced subsequent to the removal of NB325 from the cell culture medium. The present studies were conducted to determine the extent and mechanism of this prolonged antiviral activity. Persistent inhibition of HIV-1 infection by NB325 was concentration dependent and was apparent up to 8 h after removal of the compound. Flow cytometric analyses of stimulated CD4 ؉ T lymphocytes exposed to NB325 demonstrated concentration-dependent reductions in CXCR4 extracellular loop 2 epitope recognition that were maintained up to 24 h after removal of the compound. CXCL12-induced chemotaxis was also persistently inhibited following pre-exposure to NB325. These results demonstrate that persistent inhibition of X4 HIV-1 infection by NB325 involves extended perturbation of the viral coreceptor CXCR4.

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“…A variety of compounds have been proposed as potential topical anti-HIV microbicides (16,21,40,41,44,(54)(55)(56)(57). One of these is the nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781, which we and others have shown to possess excellent anti-HIV-1 microbicidal activity against wild-type (wt) HIV-1 in vitro (7,10,15,22,39,42,43).…”

mentioning

confidence: 99%

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

Hossain

Parniak

2006

J Virol

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The nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 is under development as a microbicide to prevent sexual transmission of the human immunodeficiency virus type 1 (HIV-1). However, NNRTIresistant HIV-1 is increasingly prevalent in the infected population, and one of the concerns for NNRTI-based microbicides is that they will be ineffective against drug-resistant virus and may in fact selectively transmit NNRTI-resistant virus. We evaluated the microbicidal activity of UC781 against UC781-resistant (UCR), efavirenz-resistant (EFVR), and nevirapine-resistant (NVPR) strains in a variety of microbicide-relevant tests, including inactivation of cell-free virus, inhibition of cell-to-cell HIV-1 transmission, and the ability of UC781 pretreatment to protect cells from subsequent infection in the absence of exogenous drug. UC781 was 10-to 100-fold less effective against NNRTI-resistant HIV-1 compared to wild-type (wt) virus in each of these tests, with UC781 microbicidal activity against the various virus strains being wt > NVPR > UCR > EFVR. Breakthrough experiments using UC781-pretreated cells and mixtures of wt and NNRTI-resistant HIV-1 showed that UC781-pretreatment selected for NNRTI-resistant HIV-1. However, the efficacy of UC781 was dose dependent, and 25 M UC781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wt virus. The amount of UC781 in topical microbicide formulations under current development is approximately 100-fold greater than this concentration, so transmission of NNRTI-resistant virus may not be an issue at these microbicide formulation levels of UC781. Nonetheless, the reduced microbicidal activity of UC781 against NNRTI-resistant HIV-1 suggests that additional antiviral agents should be included in NNRTIbased microbicide formulations.

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A Series of Diaryltriazines and Diarylpyrimidines Are Highly Potent Nonnucleoside Reverse Transcriptase Inhibitors with Possible Applications as Microbicides

Cited by 56 publications

References 28 publications

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Persistent Interactions between Biguanide-Based Compound NB325 and CXCR4 Result in Prolonged Inhibition of Human Immunodeficiency Virus Type 1 Infection

In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

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