Inhibition of Human Immunodeficiency Virus Type 1 Tat-
            <i>trans</i>
            -Activation-Responsive Region Interaction by an Antiviral Quinolone Derivative

Richter, Sara N.; Parolin, Cristina; Gatto, Barbara; Vecchio, Claudia Del; Brocca-Cofano, Egidio; Fravolini, Arnaldo; Palù, Giorgio; Palumbo, Manlio

doi:10.1128/aac.48.5.1895-1899.2004

Cited by 39 publications

(36 citation statements)

References 36 publications

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“…Several compounds that possess anti-HIV activity in vitro, such as quinoline derivatives TR-87, K-37, and WM5, stilbene derivative CGA137053, and substituted purines (5,27,30,56,74), have been identified as inhibiting Tat transactivity by obstructing Tat/TAR binding, whereas others, such as flavopiridol, roscovitine, and indirubin-3Ј-monoxime (12,28,68), were shown to inhibit Tat transactivity by targeting the p-TEFb component CDK9. Based on our finding, BPRHIV001 could inhibit Tat function through modulating the PI3K/Akt pathway, which has been shown to be essential in HIV replication (17,23).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

Lin

et al. 2011

J Virol

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The human immunodeficiency virus type 1 (HIV-1)-encoded RNA-binding protein Tat is known to play an essential role in viral gene expression. In the search for novel compounds to inhibit Tat transactivity, one coumarin derivative, BPRHIV001, was identified, with a 50% effective concentration (EC 50 ) against HIV-1 at 1.3 nM. BPRHIV001 is likely to exert its effects at the stage after initiation of RNAPII elongation since Tat protein expression and the assembly of the Tat/P-TEFb complex remained unchanged. Next, a reduction of the p300 protein level, known to modulate Tat function through acetylation, was observed upon BPRHIV001 treatment, while the p300 mRNA level was unaffected. A concordant reduction of phosphorylated Akt, which was shown to be closely related to p300 stability, was observed in the presence of BPRHIV001 and was accompanied by a decrease of phosphorylated PDPK1, a well-known Akt activator. Furthermore, the docking analysis revealed that the reduced PDPK1 phosphorylation likely resulted from the allosteric effect of interaction between BPRHIV001 and PDPK1. With strong synergistic effects with current reverse transcriptase inhibitors, BPRHIV001 has the potential to become a promising lead compound for the development of a novel therapeutic agent against HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

Lin

et al. 2011

J Virol

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“…Thus, through indirect antioxidant effects or direct effects on zinc trafficking, CQ may have significant effects on cellular metabolism. In addition, independent of chelation, quinols similar to CQ have been found to bind to RNA and modulate RNAprotein interactions (52). Thus, CQ might influence mutant protein accumulation and cell survival through chelation of iron, copper, zinc, or other ion or through direct interactions with RNA or protein, by stabilizing secondary structures or interfering with RNA-protein interactions or by other effects.…”

Section: Discussionmentioning

confidence: 99%

Clioquinol down-regulates mutant huntingtin expressionin vitroand mitigates pathology in a Huntington's disease mouse model

Nguyen

Hamby

Massa

2005

Proc. Natl. Acad. Sci. U.S.A.

180

107

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In investigating the role of metal ions in the pathogenesis of Huntington's disease, we examined the effects of clioquinol, a metal-binding compound currently in clinical trials for Alzheimer's disease treatment, on mutant huntingtin-expressing cells. We found that PC12 cells expressing polyglutamine-expanded huntingtin exon 1 accumulated less mutant protein and showed decreased cell death when treated with clioquinol. This effect was polyglutamine-length-specific and did not alter mRNA levels or protein degradation rates. Clioquinol treatment of transgenic Huntington's mice (R6͞2) improved behavioral and pathologic phenotypes, including decreased huntingtin aggregate accumulation, decreased striatal atrophy, improved rotarod performance, reduction of weight loss, normalization of blood glucose and insulin levels, and extension of lifespan. Our results suggest that clioquinol is a candidate therapy for Huntington's disease and other polyglutamine-expansion diseases.polyglutamine ͉ small-molecule therapeutics ͉ R6/2 transgenic mice H untington's disease (HD) is an autosomal dominant neurological disorder that causes progressive cognitive, motor, and psychiatric dysfunction over a 10-to 20-year disease course, leading to death (1, 2). HD is caused by CAG-repeat expansion (3) in the 5Ј region of the IT15 gene that encodes the ubiquitously expressed 350-kDa protein huntingtin (Htt). The expanded-CAG region encodes polyglutamine (polyQ). When the polyQ region is 40 residues or more, there is virtually 100% penetrance of the disease phenotype (4). The physiologic roles of Htt are not fully understood; however, it was recently found to be important for vesicular transport of brain-derived neurotrophic factor in axons (5).The toxicity of polyQ-Htt appears to involve a gain-offunction (6) mechanism with possible adjunct involvement of impairment of physiologic Htt function (7). Recent studies suggest that diffusely distributed mono-or oligomeric Htt is the predominant toxic form and not the highly aggregated forms present in inclusion bodies (8-11). New toxic activities may occur because the region containing the expanded polyQ tract binds to itself and other polyQ-containing proteins, especially when cleaved from the full-length protein (12), and may sequester and deactivate transcription factors such as TBP (13), CBP (14), Sp1, and TAFII130 (15). Mutant Htt is also implicated in mitochondrial function defects, including initiation of the mitochondrial permeability transition (16, 17) and loss of trophic support due to decreased production (18, 19) and dominant-negative inhibition of transport of brain-derived neurotrophic factor (5). However, the relative contributions to pathogenesis of the many potentially toxic effects of polyQ expansion of Htt have yet to be determined.Ongoing synthesis of mutant protein appears necessary to drive the pathogenic process. Yamamoto et al. (20), using a tetregulatable transgenic system, found that when expression of polyQ-htt exon 1 was inhibited in symptomatic mice, the neuropatholog...

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“…K-37 was an inhibitor of not only Tat but also other RNA-dependent transactivators. Although its target molecule remains to be elucidated, the aminoquinolone WM5, which is structurally related to K-37, was found to interact with the bulge region of the TAR (Parolin et al, 2003;Richter et al, 2004).…”

confidence: 99%

Potent and Selective Inhibition of Tat-Dependent HIV-1 Replication in Chronically Infected Cells by a Novel Naphthalene Derivative JTK-101

Wang

Yamataka

Okamoto

et al. 2007

Antivir Chem Chemother

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In search for effective human immunodeficiency virus type 1 (HIV-1) transcription inhibitors, we have evaluated more than 100,000 compounds for their inhibitory effects on HIV-1 long terminal repeat (LTR)-driven reporter gene expression, and identified a novel naphthalene derivative, JTK-101. This compound could suppress tumour necrosis factor (TNF)-α-induced HIV-1 production in latently infected OM-10.1 cells at nanomolar concentrations. JTK-101 could also potently inhibit constitutive HIV-1 production in MOTL-4/IIIB. However, the antiviral activity of JTK-101 was found to be much weaker in acutely infected cells and the chronically infected cells U937/IIIB cells than in OM-10.1 and MOLT-4/IIIB cells. JTK-101 selectively suppressed TNF-α-induced HIV-1 mRNA synthesis in OM-10.1 cells in a dose-dependent fashion. JTK-101 modestly inhibited TNF-α-induced HIV-1 LTR-driven reporter gene expression, but potently inhibited Tat-induced gene expression. Immunoblot analysis revealed that low-level expression of the Tat cofactors CDK9 and cyclin T1 might contribute to the diminished antiviral activity in U937/IIIB cells. Furthermore, JTK-101 could not inhibit HIV-1 replication in chronically infected monocytes/macrophages, in which CDK9 and cyclin T1 were undetectable. These results suggest that JTK-101 exerts its anti-HIV-1 activity through the inhibition of known or unknown Tat cofactors, presumably CDK9/cyclin T1.

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Inhibition of Human Immunodeficiency Virus Type 1 Tat- trans -Activation-Responsive Region Interaction by an Antiviral Quinolone Derivative

Cited by 39 publications

References 36 publications

Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

Inhibition of HIV-1 Tat-Mediated Transcription by a Coumarin Derivative, BPRHIV001, through the Akt Pathway

Clioquinol down-regulates mutant huntingtin expressionin vitroand mitigates pathology in a Huntington's disease mouse model

Potent and Selective Inhibition of Tat-Dependent HIV-1 Replication in Chronically Infected Cells by a Novel Naphthalene Derivative JTK-101

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