Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein

Strating, Jeroen R.P.M.; Linden, Lonneke van der; Albulescu, Lucian; Bigay, Joëlle; Arita, Minetaro; Delang, Leen; Leyssen, Pieter; Schaar, Hilde M. van der; Lanke, Kjerstin; Thibaut, Hendrik Jan; Ulferts, Rachel; Drin, Guillaume; Schlinck, Nina; Wubbolts, Richard; Sever, Navdar; Head, Sarah A.; Liu, Jun O.; Beachy, Philip A.; Matteis, Maria Antonietta De; Shair, Matthew D.; Olkkonen, Vesa M.; Neyts, Johan; Kuppeveld, Frank J. M. van

doi:10.1016/j.celrep.2014.12.054

Cited by 215 publications

(289 citation statements)

References 44 publications

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“…Additionally, others have shown that ITA affects the glycosylation and trafficking of other cell surface molecules including CD14 and Fc receptors; however, the relevant cellular target responsible for ITA's effects on receptor trafficking remains unknown (36,37). Recently, others have reported that ITA inhibits enterovirus replication by binding to oxysterol binding protein (OSBP) and that ITA modulates mTORC1 activity by inhibiting the mitochondrial protein voltagedependent anion channel 1 (VDAC1) (38,39). Further mechanistic deconvolution of ITA should clarify whether additional cell types and/or physiological responses might contribute to the antifibrotic efficacy observed in vivo, an important limitation to the current study.…”

Section: Discussionmentioning

confidence: 99%

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Bollong

Yang

Vergani

et al. 2017

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

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Fibrosis, a disease in which excessive amounts of connective tissue accumulate in response to physical damage and/or inflammatory insult, affects nearly every tissue in the body and can progress to a state of organ malfunction and death. A hallmark of fibrotic disease is the excessive accumulation of extracellular matrix-secreting activated myofibroblasts (MFBs) in place of functional parenchymal cells. As such, the identification of agents that selectively inhibit the transdifferentiation process leading to the formation of MFBs represents an attractive approach for the treatment of diverse fibrosis-related diseases. Herein we report the development of a high throughput image-based screen using primary hepatic stellate cells that identified the antifungal drug itraconazole (ITA) as an inhibitor of MFB cell fate in resident fibroblasts derived from multiple murine and human tissues (i.e., lung, liver, heart, and skin). Chemical optimization of ITA led to a molecule (CBR-096-4) devoid of antifungal and human cytochrome P450 inhibitory activity with excellent pharmacokinetics, safety, and efficacy in rodent models of lung, liver, and skin fibrosis. These findings may serve to provide a strategy for the safe and effective treatment of a broad range of fibrosis-related diseases.

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Section: Discussionmentioning

confidence: 99%

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Bollong

Yang

Vergani

et al. 2017

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

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“…During the review process, we became aware that Strating and coworkers addressed ITZ activity against enterovirus using CVB3 as a model (47). ITZ and posaconazole could serve as important tools for understanding the fundamental aspects of the formation and function of enterovirus replication complexes.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Itraconazole with Broad-Spectrum In Vitro Antienterovirus Activity That Targets Nonstructural Protein 3A

Gao

Yuan

Zhang

et al. 2015

Antimicrob Agents Chemother

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There is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections, which remain a substantial threat to public health. To discover inhibitors that can be immediately repurposed for treatment of enterovirus infections, we developed a high-throughput screening assay that measures the cytopathic effect induced by enterovirus 71 (EV71) to screen an FDA-approved drug library. Itraconazole (ITZ), a triazole antifungal agent, was identified as an effective inhibitor of EV71 replication in the low-micromolar range (50% effective concentrations [EC 50 s], 1.15 M). Besides EV71, the compound also inhibited other enteroviruses, including coxsackievirus A16, coxsackievirus B3, poliovirus 1, and enterovirus 68. Study of the mechanism of action by time-of-addition assay and transient-replicon assay revealed that ITZ targeted a step involved in RNA replication or polyprotein processing. We found that the mutations (G5213U and U5286C) conferring the resistance to the compound were in nonstructural protein 3A, and we confirmed the target amino acid substitutions (3A V51L and 3A V75A) using a reverse genetic approach. Interestingly, posaconazole, a new oral azole with a molecular structure similar to that of ITZ, also exhibited anti-EV71 activity. Moreover, ITZ-resistant viruses do not exhibit cross-resistance to posaconazole or the enviroxime-like compound GW5074, which also targets the 3A region, indicating that they may target a specific site(s) in viral genome. Although the protective activity of ITZ or posaconazole (alone or in combination with other antivirals) remains to be assessed in animal models, our findings may represent an opportunity to develop therapeutic interventions for enterovirus infection.

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“…This family of proteins bind and transfer sterols between cellular organelles, such as the Golgi and ER membranes (Mesmin et al 2013). Interestingly, RNA viruses have been shown to coopt OSBP and ORPs to facilitate assembly (Amako et al 2009) and (or) to shuttle and enrich cholesterol at sites of viral replication (Barajas et al 2014;Wang et al 2014;Strating et al 2015). In fact, small molecule targeting of OSBP has shown broad-range efficacy in inhibition of enterovirus replication (Strating et al 2015).…”

Section: Interactions With Oxysterol Binding Proteinsmentioning

confidence: 99%

“…Interestingly, RNA viruses have been shown to coopt OSBP and ORPs to facilitate assembly (Amako et al 2009) and (or) to shuttle and enrich cholesterol at sites of viral replication (Barajas et al 2014;Wang et al 2014;Strating et al 2015). In fact, small molecule targeting of OSBP has shown broad-range efficacy in inhibition of enterovirus replication (Strating et al 2015). In the absence of viral infection, 25HC relocalizes OSBP from the cytoplasm to the Golgi (Ridgway et al 1992).…”

Section: Interactions With Oxysterol Binding Proteinsmentioning

confidence: 99%

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

2015

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Abstract:The metabolic interplay between hosts and viruses plays a crucial role in determining the outcome of viral infection. Viruses reorchestrate the host's primary metabolic gene networks, including genes associated with mevalonate and isoprenoid synthesis, to acquire the necessary energy and structural components for their viral life cycles. Recent work has demonstrated that the interferon-mediated antiviral response suppresses the sterol pathway through production of a signalling molecule, 25-hydroxycholesterol (25HC). This oxysterol has been shown to exert multiple effects, both through incorporation into host cellular membranes as well as through transcriptional control. Herein, we summarize our current understanding of the multifunctional roles of 25HC in the mammalian innate antiviral response.Key words: 25-hydroxycholesterol, cholesterol-25-hydroxylase, metabolism, virus, immunity.Résumé : Les interactions métaboliques entre les hôtes et les virus jouent un rôle crucial qui déterminera l'issue de l'infection virale. Les virus réorganisent les réseaux de gènes métaboliques primaires de l'hôte, dont les gènes liés à la synthèse du mévalonate et des isoprénoïdes, afin d'acquérir l'énergie et les éléments structuraux néces-saires à leur cycle de vie. Des travaux récents ont démontré que la réponse antivirale activée par les interférons supprime la voie des stérols par la production d'une molécule de signalisation, le 25-hydroxycholestérol (25HC). On a révélé que cet oxystérol avait plus d'un effet, tant par son intégration dans les membranes de la cellule-hôte que par le contrôle de la transcription. Nous résumons ici notre conception actuelle des rôles multifonctionnels du 25HC dans la réponse antivirale innée chez les mammifères. [Traduit par la Rédaction] -clés : 25-hydroxycholestérol, cholestérol-25-hydroxylase, métabolisme, virus, immunité. Mots

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Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein

Cited by 215 publications

References 44 publications

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

Discovery of Itraconazole with Broad-Spectrum In Vitro Antienterovirus Activity That Targets Nonstructural Protein 3A

Armand-Frappier Outstanding Student Award — The emerging role of 25-hydroxycholesterol in innate immunity

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