Replication and Inhibitors of Enteroviruses and Parechoviruses

Linden, Lonneke van der; Wolthers, Katja C.; Kuppeveld, Frank J. M. van

doi:10.3390/v7082832

Cited by 119 publications

(70 citation statements)

References 215 publications

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“…than any virus lacking this mutation. Picornaviruses replicate their RNA on reorganized cellular membrane structures designated “replication organelles.” The virus-induced lipid composition of these regions differs significantly from normal cellular membranes (Belov, 2014; van der Linden et al, 2015). For enteroviruses, including the RV, non-structural proteins 2BC and 3A display hydrophobic domains that are somehow involved in this process of internal membrane rearrangement, presumably through interactions with a number of host cell proteins.…”

Section: Discussionmentioning

confidence: 95%

“…For enteroviruses, including the RV, non-structural proteins 2BC and 3A display hydrophobic domains that are somehow involved in this process of internal membrane rearrangement, presumably through interactions with a number of host cell proteins. These include Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1), phosphatidylinositol 4-kinase type III β (PI4KIIIβ) and the Golgi adaptor protein acyl-CoA-binding domain-containing protein 3 (ACBD3) (Wessels et al, 2006; van der Linden et al, 2015). It has been demonstrated that transient expression of an A16 3A protein by transfection, can lead to disruption of the Golgi structure and inhibition of cellular protein secretion (Mousnier et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Mutations in VP1 and 3A proteins improve binding and replication of rhinovirus C15 in HeLa-E8 cells

et al. 2016

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Viruses in the rhinovirus C species (RV-C) can cause severe respiratory illnesses in children including pneumonia and asthma exacerbations. A transduced cell line (HeLa-E8) stably expressing the CDHR3-Y529 receptor variant, supports propagation of RV-C after infection. C15 clinical or recombinant isolates replicate in HeLa-E8, however progeny yields are lower than those of related strains of RV-A and RV-B. Serial passaging of C15 in HeLa-E8 resulted in stronger cytopathic effects and increased (≥ 10-fold) virus binding to cells and progeny yields. The adaptation was acquired by two mutations which increased binding (VP1 T125K) and replication (3A E41K), respectively. A similar 3A mutation engineered into C2 and C41 cDNAs also improved viral replication (2–8 fold) in HeLa but the heparan sulfate mediated cell-binding enhancement by the VP1 change was C15-specific. The findings now enable large-scale cost-effective C15 production by infection and the testing of RV-C infectivity by plaque assay.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Mutations in VP1 and 3A proteins improve binding and replication of rhinovirus C15 in HeLa-E8 cells

et al. 2016

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“…Several compounds have progressed into clinical trials, but none of them has been formally approved by the FDA due to limited efficacy or safety concerns (14)(15)(16)(17). Combining antiviral agents with additive or synergistic antiviral effects is a proven strategy to increase antiviral potency and reduce potential toxicity and adverse effects.…”

mentioning

confidence: 99%

In Vitro Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71

Wang

Yuan

et al. 2016

Antimicrob Agents Chemother

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Enterovirus 71 (EV-A71) is a major causative pathogen of hand, foot, and mouth disease (HFMD) epidemics. No antiviral therapies are currently available for treating EV-A71 infections. Here, we selected five reported enterovirus inhibitors (suramin, itraconazole [ITZ], GW5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit EV-A71 replication alone and in combination. All selected compounds have anti-EV-A71 activities in cell culture. The combination of rupintrivir and ITZ or favipiravir was synergistic, while the combination of rupintrivir and suramin was additive. The combination of suramin and favipiravir exerted a strong synergistic antiviral effect. The observed synergy was not due to cytotoxicity, as there was no significant increase in cytotoxicity when compounds were used in combinations at the tested doses. To investigate the potential inhibitory mechanism of favipiravir against enterovirus, two favipiravir-resistant EV-A71 variants were independently selected, and both of them carried an S121N mutation in the finger subdomain of the 3D polymerase. Reverse engineering of this 3D S121N mutation into an infectious clone of EV-A71 confirmed the resistant phenotype. Moreover, viruses resistant to ITZ or favipiravir remained susceptible to other inhibitors. Most notably, combined with ITZ, rupintrivir prevented the development of ITZ-resistant variants. Taken together, these results provide a rational basis for the design of combination regimens for use in the treatment of EV-A71 infections.

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“…Thus, there is rationale to continue to identify and characterize new antipolioviral agents for ultimate development of therapeutic drugs against PV infections. 17 …”

mentioning

confidence: 99%

Cell-Based High-Throughput Screening Assay Identifies 2′,2′-Difluoro-2′-deoxycytidine Gemcitabine as a Potential Antipoliovirus Agent

Zhang

Yang

et al. 2016

ACS Infect. Dis.

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As we approach the global eradication of circulating wild-type polioviruses (PV), vaccination with oral poliovirus vaccine (OPV) has led to the emergence of circulating vaccine-derived poliovirus (cVDPV) and vaccine-associated paralytic poliomyelitis (VAPP). Complete cessation of all poliovirus infections may require stopping use of OPV and formulating improved vaccines and new antiviral drugs. Currently, no licensed drugs are available to treat chronically infected poliovirus excretors. Here, we created a modified PV expressing Gaussia Luciferase (Sb-Gluc) and developed a cell-based high-throughput screening (HTS) antiviral assay. Using the validated HTS assay, we screened the FDA-approved drug library of compounds and identified candidate agents capable of inhibiting PV replication. We then characterized antipoliovirus activity for the best hit, gemcitabine, a nucleoside analogue used in tumor chemotherapy. We found that gemcitabine inhibited PV Mahoney replication with an IC50 of 0.3 μM. It completely protected HeLa cells from PV-induced cytopathic effects at 25 μM, without detectable toxicity for cell viability. Furthermore, a gemcitabine metabolite directly inhibited the ability of PV RNA polymerase to synthesize or elongate PV RNA. Because PV RNA polymerase is somehow conserved among species in the Picornaviridae family, gemcitabine may be further developed as an attractive broad-spectrum antiviral for PV and others.

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Replication and Inhibitors of Enteroviruses and Parechoviruses

Cited by 119 publications

References 215 publications

Mutations in VP1 and 3A proteins improve binding and replication of rhinovirus C15 in HeLa-E8 cells

Mutations in VP1 and 3A proteins improve binding and replication of rhinovirus C15 in HeLa-E8 cells

In Vitro Assessment of Combinations of Enterovirus Inhibitors against Enterovirus 71

Cell-Based High-Throughput Screening Assay Identifies 2′,2′-Difluoro-2′-deoxycytidine Gemcitabine as a Potential Antipoliovirus Agent

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