scholarly journals In VitroAssessment of Combinations of Enterovirus Inhibitors against Enterovirus 71

2016 ◽  
Vol 60 (9) ◽  
pp. 5357-5367 ◽  
Author(s):  
Yizhuo Wang ◽  
Guiming Li ◽  
Shilin Yuan ◽  
Qianqian Gao ◽  
Ke Lan ◽  
...  
Keyword(s):  
Infectious Clone ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Mechanisms Of Action ◽  
Rational Basis ◽  
Inhibitory Mechanism ◽  
Antiviral Therapies ◽  
Resistant Phenotype ◽  
Combination Regimens

ABSTRACTEnterovirus 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.

scholarly journals Antidepressant Sertraline is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry Through Neutralization of Endolysosomal Acidification

2021 ◽  
Author(s):  
Kuan-Chi Tseng ◽  
Bang-Yan Hsu ◽  
Pin Ling ◽  
Wen-Wen Lu ◽  
Cheng-Wen Lin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Broad Spectrum ◽  
Culture Media ◽  
Antiviral Drug ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Low Ph

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs to treat EV71 infections. In this study, we conducted an antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be relieved greatly by exposing virus-infected cells to extracellular low-pH culture media. Together, we have identified an FDA-approved antidepressant with the new indication for the broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

scholarly journals Temperature-sensitive mutants of enterovirus 71 show attenuation in cynomolgus monkeys

2005 ◽  
Vol 86 (5) ◽  
pp. 1391-1401 ◽  
Author(s):  
Minetaro Arita ◽  
Hiroyuki Shimizu ◽  
Noriyo Nagata ◽  
Yasushi Ami ◽  
Yuriko Suzaki ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Virulent Strain ◽  
Infectious Clone ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Infection Model ◽  
Temperature Sensitive ◽  
Cynomolgus Monkeys

Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease and is sometimes associated with serious neurological disorders. In this study, an attempt was made to identify molecular determinants of EV71 attenuation of neurovirulence in a monkey infection model. An infectious cDNA clone of the virulent strain of EV71 prototype BrCr was constructed; temperature-sensitive (ts) mutations of an attenuated strain of EV71 or of poliovirus (PV) Sabin vaccine strains were then introduced into the infectious clone. In vitro and in vivo phenotypes of the parental and mutant viruses were analysed in cultured cells and in cynomolgus monkeys, respectively. Mutations in 3D polymerase (3Dpol) and in the 3′ non-translated region (NTR), corresponding to ts determinants of Sabin 1, conferred distinct temperature sensitivity to EV71. An EV71 mutant [EV71(S1-3′)] carrying mutations in the 5′ NTR, 3Dpol and in the 3′ NTR showed attenuated neurovirulence, resulting in limited spread of virus in the central nervous system of monkeys. These results indicate that EV71 and PV1 share common genetic determinants of neurovirulence in monkeys, despite the distinct properties in their original pathogenesis.

scholarly journals Antidepressant Sertraline Is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry through Neutralization of Endolysosomal Acidification

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 109
Author(s):  
Kuan-Chi Tseng ◽  
Bang-Yan Hsu ◽  
Pin Ling ◽  
Wen-Wen Lu ◽  
Cheng-Wen Lin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Broad Spectrum ◽  
Culture Media ◽  
Antiviral Drug ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Low Ph

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs as of yet to treat EV71 infections. In this study, we conducted antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be greatly relieved by exposing virus-infected cells to extracellular low-pH culture media. Ultimately, we have identified a use for an FDA-approved antidepressant in broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

scholarly journals DNA aptamer against EV-A71 VP1 protein: selection and application

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xinran Zou ◽  
Jing Wu ◽  
Jiaqi Gu ◽  
Li Shen ◽  
Lingxiang Mao
Keyword(s):  
Protein Expression ◽  
Enterovirus 71 ◽  
Virus Detection ◽  
Foot And Mouth Disease ◽  
High Specificity ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Dna Aptamer ◽  
Manufacturing Cost

Abstract Background Enterovirus 71 (EV-A71) is a highly infectious pathogen associated with hand, foot and mouth disease, herpangina, and various neurological complications, so it is important for the early detection and treatment of EV-A71. An aptamer is a nucleotide sequence that screened in vitro by the technology named systematic evolution of ligands by exponential enrichment technology (SELEX). Similar to antibodies, aptamers can bind to the targets with high specificity and affinity. Besides, emerging aptamers have many advantages comparing with antibodies, such as ease of synthesis and modification, having a wide variety of target materials, low manufacturing cost and easy flexibility in amending. Therefore, aptamers are promising in virus detection and anti-virus therapy. Methods Aptamers were selected by SELEX. Specificity, affinity and second structure were used to characterize the selected aptamers. Chemiluminescence was adopted to build an aptamer-based detection method for EV-A71. Cytopathogenic effects trial, the level of intracellular EV-A71 RNA and protein expression were used to evaluate the antiviral effect of the selected aptamers. Results Three DNA aptamers with high specificity and affinity for EV-A71structual protein VP1 were screened out. A rapid chemiluminutesescence aptamer biosensor for EV-A71 detection was designed out. The selected aptamers could inhibit the RNA replication and protein expression of EV-A71 in RD cells and ameliorate the cytopathogenic effects. Conclusions The aptamers against EV-A71 have the potentiality to be applied as attractive candidates used for EV-A71 detection and treatment in the future.

scholarly journals Engineering viable foot-and-mouth disease viruses with increased acid stability facilitate the development of improved vaccines

2020 ◽  
Vol 104 (4) ◽  
pp. 1683-1694 ◽  
Author(s):  
Hong Yuan ◽  
Pinghua Li ◽  
Huifang Bao ◽  
Pu Sun ◽  
Xingwen Bai ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Infectious Clone ◽  
Foot And Mouth Disease ◽  
Acid Resistance ◽  
Mouth Disease ◽  
Acid Stability ◽  
Intact Virion ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Negative Effect

AbstractFoot-and-mouth disease virus (FMDV), the most acid-unstable virus among picornaviruses, tends to disassemble into pentamers at pH values slightly below neutrality. However, the structural integrity of intact virion is one of the most important factors that influence the induction of a protective antibody response. Thus, improving the acid stability of FMDV is required for the efficacy of vaccine preparations. According to the previous studies, a single substitution or double amino acid substitutions (VP1 N17D, VP2 H145Y, VP2 D86H, VP3 H142D, VP3 H142G, and VP1 N17D + VP2 H145Y) in the capsid were introduced into the full-length infectious clone of type O FMDV vaccine strain O/HN/CHN/93 to develop seed FMDV with improved acid stability. After the transfection into BSR/T7 cells of constructed plasmids, substitution VP1 N17D or VP2 D86H resulted in viable and genetically stable FMDVs, respectively. However, substitution VP2 H145Y or VP1 N17D + VP2 H145Y showed reverse mutation and additional mutations, and substitution VP3 H141G or VP3 H141D prevented viral viability. We found that substitution VP1 N17D or VP2 D86H could confer increased acid resistance, alkali stability, and thermostability on FMDV O/HN/CHN/93, whereas substitution VP1 N17D was observed to lead to a decreased replication ability in BHK-21 cells and mildly impaired virulence in suckling mice. In contrast, substitution VP2 D86H had no negative effect on viral infectivity. These results indicated that the mutant rD86H carrying substitution VP2 D86H firstly reported by us could be more adequate for the development of inactivated FMD vaccines with enhanced acid stability.

scholarly journals DNA methylation and SNP in IFITM3 are correlated with hand, foot and mouth disease caused by enterovirus 71

2021 ◽  
Vol 105 ◽  
pp. 199-208
Author(s):  
Mei Li ◽  
Ya-Ping Li ◽  
Hui-Ling Deng ◽  
Mu-Qi Wang ◽  
Yuan Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Foot And Mouth

scholarly journals Advances in Antigenic Peptide-Based Vaccine and Neutralizing Antibodies against Viruses Causing Hand, Foot, and Mouth Disease

2019 ◽  
Vol 20 (6) ◽  
pp. 1256 ◽  
Author(s):  
Mohd Anasir ◽  
Chit Poh
Keyword(s):  
Neutralizing Antibodies ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Antigenic Peptide ◽  
Effective Vaccine ◽  
Inactivated Vaccine ◽  
Antigenic Peptides ◽  
Foot And Mouth ◽  
Etiological Agents

Hand, foot, and mouth disease (HFMD) commonly produces herpangina, but fatal neurological complications have been observed in children. Enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16) are the predominant viruses causing HFMD worldwide. With rising concern about HFMD outbreaks, there is a need for an effective vaccine against EV-A71 and CV-A16. Although an inactivated vaccine has been developed against EV-A71 in China, the inability of the inactivated vaccine to confer protection against CV-A16 infection and other HFMD etiological agents, such as CV-A6 and CV-A10, necessitates the exploration of other vaccine platforms. Thus, the antigenic peptide-based vaccines are promising platforms to develop safe and efficacious multivalent vaccines, while the monoclonal antibodies are viable therapeutic and prophylactic agents against HFMD etiological agents. This article reviews the available information related to the antigenic peptides of the etiological agents of HFMD and their neutralizing antibodies that can provide a basis for the design of future therapies against HFMD etiological agents.

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