PD 404,182 Is a Virocidal Small Molecule That Disrupts Hepatitis C Virus and Human Immunodeficiency Virus

Chamoun, Ana Maria; Chockalingam, Karuppiah; Bobardt, Michael; Simeon, Rudo; Chang, Jinhong; Gallay, Philippe; Chen, Zhilei

doi:10.1128/aac.05722-11

Cited by 36 publications

(35 citation statements)

References 47 publications

(47 reference statements)

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“…The compound concentration used in this study (50-100 mM) did not perturb cell membrane integrity (as demonstrated by lack of lactate dehydrogenase leakage into the conditioned media) (Supplemental Fig. 1) or induce cytotoxicity, as demonstrated by standard trypan blue staining, a finding that is validated by a previous report on several human cell lines (Chamoun et al, 2012). Interestingly, PD 404182 has been reported to inhibit EC sprouting in response to the potent proangiogenic protein vascular endothelial growth factor (VEGF) (Kalén et al, 2009), suggesting its therapeutic potential in pathologic angiogenesis.…”

Section: Resultssupporting

confidence: 62%

A Novel and Potent Inhibitor of Dimethylarginine Dimethylaminohydrolase: A Modulator of Cardiovascular Nitric Oxide

Ghebremariam¹,

Erlanson²,

Cooke³

2013

J Pharmacol Exp Ther

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3,4, [1,2-c]- [1,3]benzothiazine], a heterocyclic iminobenzothiazine derivative, is a member of the Library of Pharmacologically Active Compounds (LOPAC) that is reported to possess antimicrobial and anti-inflammatory properties. In this study, we used biochemical assays to screen LOPAC against human dimethylarginine dimethylaminohydrolase isoform 1 (DDAH1), an enzyme that physiologically metabolizes asymmetric dimethylarginine (ADMA), an endogenous and competitive inhibitor of nitric oxide (NO) synthase. We discovered that PD 404182 directly and dosedependently inhibits DDAH. Moreover, PD 404182 significantly increased intracellular levels of ADMA in cultured primary human vascular endothelial cells (ECs) and reduced lipopolysaccharideinduced NO production in these cells, suggesting its therapeutic potential in septic shock-induced vascular collapse. In addition, PD 404182 abrogated the formation of tube-like structures by ECs in an in vitro angiogenesis assay, indicating its antiangiogenic potential in diseases characterized by pathologically excessive angiogenesis. Furthermore, we investigated the potential mechanism of inhibition of DDAH by this small molecule and found that PD 404182, which has striking structural similarity to ADMA, could be competed by a DDAH substrate, suggesting that it is a competitive inhibitor. Finally, our enzyme kinetics assay showed time-dependent inhibition, and our inhibitor dilution assay showed that the enzymatic activity of DDAH did not recover significantly after dilution, suggesting that PD 404182 might be a tightly bound, covalent, or an irreversible inhibitor of human DDAH1. This proposal is supported by mass spectrometry studies with PD 404182 and glutathione.

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Section: Resultssupporting

confidence: 62%

A Novel and Potent Inhibitor of Dimethylarginine Dimethylaminohydrolase: A Modulator of Cardiovascular Nitric Oxide

Ghebremariam¹,

Erlanson²,

Cooke³

2013

J Pharmacol Exp Ther

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“…2B). The positive control, the virucidal compound PD 404,182, reduced HCV infectivity Ͼ90% during the same period (37). These results indicate that phenothiazines do not inhibit HCV entry by inactivating the virus directly.…”

Section: Identification Of Additional Phenothiazine-like Hcv Inhibitorsmentioning

confidence: 53%

Phenothiazines Inhibit Hepatitis C Virus Entry, Likely by Increasing the Fluidity of Cholesterol-Rich Membranes

Chamoun‐Emanuelli

Pécheur

Simeon

et al. 2013

Antimicrob Agents Chemother

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Despite recent progress in the development of direct-acting antiviral agents against hepatitis C virus (HCV), more effective therapies are still urgently needed. We and others previously identified three phenothiazine compounds as potent HCV entry inhibitors. In this study, we show that phenothiazines inhibit HCV entry at the step of virus-host cell fusion, by intercalating into cholesterol-rich domains of the target membrane and increasing membrane fluidity. Perturbation of the alignment/packing of cholesterol in lipid membranes likely increases the energy barrier needed for virus-host fusion. A screening assay based on the ability of molecules to selectively increase the fluidity of cholesterol-rich membranes was subsequently developed. One compound that emerged from the library screen, topotecan, is able to very potently inhibit the fusion of liposomes with cell culture-derived HCV (HCVcc). These results yield new insights into HCV infection and provide a platform for the identification of new HCV inhibitors.

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“…C5A inhibited the entry of several enveloped viruses, including HCV and HIV (40,41), by virucidal mechanisms. Another inhibitor of HCV and HIV infectivity, PD 404182, was proposed to disrupt virions, perhaps by interfering with membrane fluidity or curvature (42). It might also act as a weak RAFI.…”

Section: Discussionmentioning

confidence: 99%

“…These approaches, unfortunately, have the same limitations as targeting any other viral protein, such as selection for resistance and narrow specificity (3). Experimental compounds have been proposed to inhibit the infectivity of unrelated enveloped viruses by disruption of virion envelopes (e.g., PD 404182 [42]), inhibition of fusion by poorly understood mechanisms (e.g., arbidol [48]), or by irreparable damage to the virion lipid envelopes (e.g., LJ-001 [49]). From these and related studies, it is clear that antiviral approaches targeting conserved structural elements of virions, such as the virion envelope, can result in broad-spectrum activity against unrelated enveloped viruses.…”

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confidence: 99%

5-(Perylen-3-yl)Ethynyl-arabino-Uridine (aUY11), an Arabino-Based Rigid Amphipathic Fusion Inhibitor, Targets Virion Envelope Lipids To Inhibit Fusion of Influenza Virus, Hepatitis C Virus, and Other Enveloped Viruses

Colpitts

Устинов

Epand

et al. 2013

J Virol

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Entry of enveloped viruses requires fusion of viral and cellular membranes. Fusion requires the formation of an intermediate stalk structure, in which only the outer leaflets are fused. The stalk structure, in turn, requires the lipid bilayer of the envelope to bend into negative curvature. This process is inhibited by enrichment in the outer leaflet of lipids with larger polar headgroups, which favor positive curvature. Accordingly, phospholipids with such shape inhibit viral fusion. We previously identified a compound, 5-(perylen-3-yl)ethynyl-2=-deoxy-uridine (dUY11), with overall shape and amphipathicity similar to those of these phospholipids. dUY11 inhibited the formation of the negative curvature necessary for stalk formation and the fusion of a model enveloped virus, vesicular stomatitis virus (VSV). We proposed that dUY11 acted by biophysical mechanisms as a result of its shape and amphipathicity. To test this model, we have now characterized the mechanisms against influenza virus and HCV of 5-(perylen-3-yl)ethynyl-arabino-uridine (aUY11), which has shape and amphipathicity similar to those of dUY11 but contains an arabino-nucleoside. aUY11 interacted with envelope lipids to inhibit the infectivity of influenza virus, hepatitis C virus (HCV), herpes simplex virus 1 and 2 (HSV-1/2), and other enveloped viruses. It specifically inhibited the fusion of influenza virus, HCV, VSV, and even protein-free liposomes to cells. Furthermore, aUY11 inhibited the formation of negative curvature in model lipid bilayers. In summary, the arabino-derived aUY11 and the deoxy-derived dUY11 act by the same antiviral mechanisms against several enveloped but otherwise unrelated viruses. Therefore, chemically unrelated compounds of appropriate shape and amphipathicity target virion envelope lipids to inhibit formation of the negative curvature required for fusion, inhibiting infectivity by biophysical, not biochemical, mechanisms.

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PD 404,182 Is a Virocidal Small Molecule That Disrupts Hepatitis C Virus and Human Immunodeficiency Virus

Abstract: We describe a virucidal small molecule, PD 404,182, that is effective against hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The median 50% inhibitory concentrations (IC

Cited by 36 publications

References 47 publications

A Novel and Potent Inhibitor of Dimethylarginine Dimethylaminohydrolase: A Modulator of Cardiovascular Nitric Oxide

A Novel and Potent Inhibitor of Dimethylarginine Dimethylaminohydrolase: A Modulator of Cardiovascular Nitric Oxide

Phenothiazines Inhibit Hepatitis C Virus Entry, Likely by Increasing the Fluidity of Cholesterol-Rich Membranes

5-(Perylen-3-yl)Ethynyl-arabino-Uridine (aUY11), an Arabino-Based Rigid Amphipathic Fusion Inhibitor, Targets Virion Envelope Lipids To Inhibit Fusion of Influenza Virus, Hepatitis C Virus, and Other Enveloped Viruses

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