Inhibitors compounds of the flavivirus replication process

García, Leidy L.; Padilla, Leonardo; Castaño, Jhon Carlos

doi:10.1186/s12985-017-0761-1

Cited by 58 publications

(46 citation statements)

References 70 publications

(257 reference statements)

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“…The obtained results are somewhat supported by the previous study using time-of-drug-addition (TOA) in which a series of phenolic compounds could interact with multiple targets at both early and late stages of the viral life cycle [21]. Since these proteins contribute to several roles in the viral life cycle, they are important targets for developing flavivirus inhibitors [18,35,53]. The NS1 protein is involved in several functions throughout the viral life cycle and immune evasion and can be used for DENV detection.…”

Section: Viral Target For Phenolic Lipid Compoundssupporting

confidence: 76%

Target Identification Using Homopharma and Network-Based Methods for Predicting Compounds Against Dengue Virus-Infected Cells

et al. 2020

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Drug target prediction is an important method for drug discovery and design, can disclose the potential inhibitory effect of active compounds, and is particularly relevant to many diseases that have the potential to kill, such as dengue, but lack any healing agent. An antiviral drug is urgently required for dengue treatment. Some potential antiviral agents are still in the process of drug discovery, but the development of more effective active molecules is in critical demand. Herein, we aimed to provide an efficient technique for target prediction using homopharma and network-based methods, which is reliable and expeditious to hunt for the possible human targets of three phenolic lipids (anarcardic acid, cardol, and cardanol) related to dengue viral (DENV) infection as a case study. Using several databases, the similarity search and network-based analyses were applied on the three phenolic lipids resulting in the identification of seven possible targets as follows. Based on protein annotation, three phenolic lipids may interrupt or disturb the human proteins, namely KAT5, GAPDH, ACTB, and HSP90AA1, whose biological functions have been previously reported to be involved with viruses in the family Flaviviridae. In addition, these phenolic lipids might inhibit the mechanism of the viral proteins: NS3, NS5, and E proteins. The DENV and human proteins obtained from this study could be potential targets for further molecular optimization on compounds with a phenolic lipid core structure in anti-dengue drug discovery. As such, this pipeline could be a valuable tool to identify possible targets of active compounds.

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Section: Viral Target For Phenolic Lipid Compoundssupporting

confidence: 76%

Target Identification Using Homopharma and Network-Based Methods for Predicting Compounds Against Dengue Virus-Infected Cells

et al. 2020

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“…Several small molecule inhibitors of flavivirus replication have been identified (Garcia, Padilla et al 2017), the majority of which are active against DENV with only a few having activity against ZIKV. These include compounds that target the viral proteins E, C, NS3, NS4, NS5 and others for which the target is yet to be defined.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

2018

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Zika virus (ZIKV) is an emerging pathogen linked to neurological disorders for which there is currently no targeted therapy. To identify host innate immune response proteins that restrict ZIKV replication, we treated monocytes and macrophages with toll-like receptor (TLR) agonists. Of those tested, the TLR7/8 agonist R848 (resiquimod) was the most potent. RNA-seq analysis identified several genes strongly induced by R848 in monocytes. Testing of several of these for their ability to restrict ZIKV replication identified viperin, an interferon-induced gene active against several viruses. Transduction of microglial CHME3 cells with a viperin lentiviral expression vector rendered them resistant to ZIKV infection, preventing the synthesis of viral RNA and protein. CRISPR/Cas9 knock-out (KO) of viperin in macrophages relieved the block to infection, demonstrating that viperin is a major innate immune response protein able to block ZIKV replication. TLR agonists may be useful for the prophylactic or therapeutic treatment for ZIKV.

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“…As currently no antiviral therapies against any flaviviruses, including WNV, have been approved, the search for inhibitory compounds is a keystone for therapeutic applications [ 39 , 40 , 41 ]. In this work, the effect of two broadly-active PKC inhibitors, calphostin C, a potent inhibitor used in the treatment of some cancer cell lines [ 42 , 43 ], and chelerythrine, with broad-spectrum biological activities, such as antimicrobial, antifungal, anti-inflammatory, and anti-tumoral effects [ 44 ], and two PKC inhibitors that have shown specific activity against conventional and novel PKC isoforms, sotrastaurine and enzastaurin, have been assayed against WNV infection in cell culture.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication

Blázquez¹,

Vázquez-Calvo²,

Martín-Acebes³

et al. 2018

Viruses

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Flaviviruses are relevant animal and human pathogens that include West Nile virus (WNV), Japanese encephalitis virus, dengue virus, or Zika virus, among others. Currently, no licensed therapy is available to fight flaviviral infections. Protein kinases C (PKCs) constitute a family of multifunctional lipid-dependent isoenzymes that regulate a wide variety of cellular processes (apoptosis, differentiation, proliferation, cellular transformation, motility, adhesion, etc.) being currently considered at the front line of drug development for the treatment of diverse human disorders. PKCs have also been implicated in different steps during viral replication; however, nowadays, results regarding their role in flavivirus replication are controversial. Here we demonstrate that calphostin C and chelerythrine, two broad-PKC inhibitors that target conventional, novel and atypical PKCs, significantly inhibit WNV multiplication in cell culture without affecting cell viability. A reduction of viral yields was observed in treated cells when compared with mock-treated cells. Likewise, immunofluorescence detection of viral enveloped E protein was reduced in treated cells, as was the amount of viral RNA released to the supernatant, mainly in those treated with chelerythrine. On the other hand, two PKC inhibitors specific for conventional and novel isoforms (staurosporine and enzastaurine) did not show any significant effect in WNV multiplication. These results suggested that PKCs, more probably atypical PKCs, are likely involved in WNV multiplication, although both broad-spectrum tested drugs seem to act through different mechanisms, and point to them as potential antiviral candidates for WNV, as well as for other related flaviviruses.

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Inhibitors compounds of the flavivirus replication process

Cited by 58 publications

References 70 publications

Target Identification Using Homopharma and Network-Based Methods for Predicting Compounds Against Dengue Virus-Infected Cells

Target Identification Using Homopharma and Network-Based Methods for Predicting Compounds Against Dengue Virus-Infected Cells

Toll-like receptor agonist R848 blocks Zika virus replication by inducing the antiviral protein viperin

Pharmacological Inhibition of Protein Kinase C Reduces West Nile Virus Replication

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