scholarly journals A Conserved Inhibitory Mechanism of a Lycorine Derivative against Enterovirus and Hepatitis C Virus

2015 ◽  
Vol 60 (2) ◽  
pp. 913-924 ◽  
Author(s):  
Yu Guo ◽  
Yaxin Wang ◽  
Lin Cao ◽  
Peng Wang ◽  
Jie Qing ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Asia Pacific ◽  
Human Hand ◽  
Content Type ◽  
Viral Proteases ◽  
Causative Agents ◽  
Multiple Strains

ABSTRACTEnterovirus 71 (EV71) (Picornaviridaefamily) and hepatitis C virus (HCV) (Flaviviridaefamily) are the causative agents of human hand, foot, and mouth disease (HFMD) and hepatitis C, resulting in a severe pandemic involving millions of infections in the Asia-Pacific region and worldwide. The great impact of EV71 and HCV on public health highlights the need to further our understanding of the biology of these two viruses and develop effective therapeutic antivirals. Here, we evaluated a total of 32 lycorine derivatives and demonstrated that 1-acetyllycorine suppressed the proliferation of multiple strains of EV71 in various cells. The results of the drug resistance analysis revealed that 1-acetyllycorine targeted a phenylalanine (F76) in EV71 2A protease (2Apro) to stabilize the conformation of a unique zinc finger. Most interestingly, the zinc binding site in EV71 2Aprois the exclusive homolog of HCV NS3 among all viruses. Further analysis revealed that 1-acetyllycorine also inhibits HCV with high efficacy, and the mutation on R118 in HCV NS3, which corresponds to F76 in EV71 2Apro, confers the resistance of HCV to 1-acetyllycorine. These results revealed a conserved mechanism of 1-acetyllycorine against EV71 and HCV through targeting viral proteases. We also documented the significant synergistic anti-EV71 and anti-HCV effects of 1-acetyllycorine with reported inhibitors, supporting potential combination therapy for the treatment of EV71 and HCV infections.

Management of hepatitis C virus infection in the Asia-Pacific region: an update

2017 ◽  
Vol 2 (1) ◽  
pp. 52-62 ◽  
Author(s):  
Seng Gee Lim ◽  
Alessio Aghemo ◽  
Pei-Jer Chen ◽  
Yock Young Dan ◽  
Edward Gane ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Asia Pacific ◽  
Pacific Region ◽  
Hepatitis C Virus Infection ◽  
Asia Pacific Region

scholarly journals Geneticin Stabilizes the Open Conformation of the 5′ Region of Hepatitis C Virus RNA and Inhibits Viral Replication

2015 ◽  
Vol 60 (2) ◽  
pp. 925-935 ◽  
Author(s):  
Ascensión Ariza-Mateos ◽  
Rosa Díaz-Toledano ◽  
Timothy M. Block ◽  
Samuel Prieto-Vega ◽  
Alex Birk ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Therapeutic Potential ◽  
Kinetic Studies ◽  
Rnase P ◽  
Start Codon ◽  
Hcv Rna ◽  
Rnase Iii ◽  
Entry Site ◽  
Content Type

ABSTRACTThe aminoglycoside Geneticin (G418) is known to inhibit cell culture proliferation, via virus-specific mechanisms, of two different virus genera from the familyFlaviviridae. Here, we tried to determine whether Geneticin can selectively alter the switching of the nucleotide 1 to 570 RNA region of hepatitis C virus (HCV) and, if so, whether this inhibits viral growth. Two structure-dependent RNases known to specifically cleave HCV RNA were tested in the presence or absence of the drug. One was theSynechocystissp. RNase P ribozyme, which cleaves the tRNA-like domain around the AUG start codon under high-salt buffer conditions; the second wasEscherichia coliRNase III, which recognizes a double-helical RNA switch element that changes the internal ribosome entry site (IRES) from a closed (C) conformation to an open (O) one. While the drug did not affect RNase P activity, it did inhibit RNase III in the micromolar range. Kinetic studies indicated that the drug favors the switch from the C to the O conformation of the IRES by stabilizing the distal double-stranded element and inhibiting further processing of the O form. We demonstrate that, because the RNA in this region is highly conserved and essential for virus survival, Geneticin inhibits HCV Jc1 NS3 expression, the release of the viral genomic RNA, and the propagation of HCV in Huh 7.5 cells. Our study highlights the crucial role of riboswitches in HCV replication and suggests the therapeutic potential of viral-RNA-targeted antivirals.

scholarly journals Phylogenetic Analysis of Enterovirus 71 Strains Isolated during Linked Epidemics in Malaysia, Singapore, and Western Australia

2001 ◽  
Vol 75 (16) ◽  
pp. 7732-7738 ◽  
Author(s):  
Peter McMinn ◽  
Katie Lindsay ◽  
David Perera ◽  
Hung Ming Chan ◽  
Kwai Peng Chan ◽  
...  
Keyword(s):  
Western Australia ◽  
Enterovirus 71 ◽  
Case Fatality ◽  
Foot And Mouth Disease ◽  
Severe Form ◽  
Asia Pacific ◽  
Pacific Region ◽  
Asia Pacific Region ◽  
Neurological Sequelae ◽  
Genetic Lineages

ABSTRACT Enterovirus 71 (EV71) is a frequent cause of hand, foot, and mouth disease (HFMD) epidemics associated with severe neurological sequelae in a small proportion of cases. There has been a significant increase in EV71 epidemic activity throughout the Asia-Pacific region since 1997. Recent HFMD epidemics in this region have been associated with a severe form of brainstem encephalitis associated with pulmonary edema and high case fatality rates. In this study, we show that four genetic lineages of EV71 have been prevalent in the Asia-Pacific region since 1997, including two previously undescribed genogroups (B3 and B4). Furthermore, we show that viruses belonging to genogroups B3 and B4 have circulated endemically in Southeast Asia during this period and have been the primary cause of several large HFMD or encephalitis epidemics in Malaysia, Singapore, and Western Australia.

In-cell selectivity profiling of membrane-anchored and replicase-associated hepatitis C virus NS3-4A protease reveals a common, stringent substrate recognition profile

2011 ◽  
Vol 392 (10) ◽  
pp. 927-935 ◽  
Author(s):  
Morgan M. Martin ◽  
Stephanie A. Condotta ◽  
Jeremy Fenn ◽  
Andrea D. Olmstead ◽  
François Jean
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Biochemical Study ◽  
Substrate Recognition ◽  
Host Cells ◽  
Protein Substrates ◽  
Viral Proteases ◽  
Endoproteolytic Cleavage ◽  
Infected Cells ◽  
Membrane Anchoring

AbstractThe need to identify anti-Flaviviridaeagents has resulted in intensive biochemical study of recombinant nonstructural (NS) viral proteases; however, experimentation on viral protease-associated replication complexes in host cells is extremely challenging and therefore limited. It remains to be determined if membrane anchoring and/or association to replicase-membrane complexes of proteases, such as hepatitis C virus (HCV) NS3-4A, plays a regulatory role in the substrate selectivity of the protease. In this study, we examined trans-endoproteolytic cleavage activities of membrane-anchored and replicase-associated NS3-4A using an internally consistent set of membrane-anchored protein substrates mimicking all known HCV NS3-4A polyprotein cleavage sequences. Interestingly, we detected cleavage of substrates encoding for the NS4B/NS5A and NS5A/NS5B junctions, but not for the NS3/NS4A and NS4A/NS4B substrates. This stringent substrate recognition profile was also observed for the replicase-associated NS3-4A and is not genotype-specific. Our study also reveals that ER-anchoring of the substrate is critical for its cleavage by NS3-4A. Importantly, we demonstrate that in HCV-infected cells, the NS4B/NS5A substrate was cleaved efficiently. The unique ability of our membrane-anchored substrates to detect NS3-4A activity alone, in replication complexes, or within the course of infection, shows them to be powerful tools for drug discovery and for the study of HCV biology.

scholarly journals Early Evidence of Inactivated Enterovirus 71 Vaccine Impact Against Hand, Foot, and Mouth Disease in a Major Center of Ongoing Transmission in China, 2011–2018: A Longitudinal Surveillance Study

2019 ◽  
Author(s):  
Jennifer R Head ◽  
Philip A Collender ◽  
Joseph A Lewnard ◽  
Nicholas K Skaff ◽  
Ling Li ◽  
...  
Keyword(s):  
Time Series ◽  
Incidence Rate ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Full Time ◽  
Study Region ◽  
Foot And Mouth ◽  
Vaccine Impact

Abstract Background Enterovirus 71 (EV71) is a major causative agent of hand, foot, and mouth disease (HFMD), associated with severe manifestations of the disease. Pediatric immunization with inactivated EV71 vaccine was initiated in 2016 in the Asia-Pacific region, including China. We analyzed a time series of HFMD cases attributable to EV71, coxsackievirus A16 (CA16), and other enteroviruses in Chengdu, a major transmission center in China, to assess early impacts of immunization. Methods Reported HFMD cases were obtained from China’s notifiable disease surveillance system. We compared observed postvaccination incidence rates during 2017–2018 with counterfactual predictions made from a negative binomial regression and a random forest model fitted to prevaccine years (2011–2015). We fit a change point model to the full time series to evaluate whether the trend of EV71 HFMD changed following vaccination. Results Between 2011 and 2018, 279 352 HFMD cases were reported in the study region. The average incidence rate of EV71 HFMD in 2017–2018 was 60% (95% prediction interval [PI], 41%–72%) lower than predicted in the absence of immunization, corresponding to an estimated 6911 (95% PI, 3246–11 542) EV71 cases averted over 2 years. There were 52% (95% PI, 42%–60%) fewer severe HFMD cases than predicted. However, the incidence rate of non-CA16 and non-EV71 HFMD was elevated in 2018. We identified a significant decline in the trend of EV71 HFMD 4 months into the postvaccine period. Conclusions We provide the first real-world evidence that programmatic vaccination against EV71 is effective against childhood HFMD and present an approach to detect early vaccine impact or intended consequences from surveillance data.

scholarly journals Structure, Immunogenicity, and Protective Mechanism of an Engineered Enterovirus 71-Like Particle Vaccine Mimicking 80S Empty Capsid

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Xiaoli Wang ◽  
Zhiqiang Ku ◽  
Xiang Zhang ◽  
Xiaohua Ye ◽  
Jinhuan Chen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Asia Pacific ◽  
Protective Mechanism ◽  
Particle Assembly ◽  
Virus Like Particle ◽  
Empty Capsid ◽  
Foot And Mouth

ABSTRACTEnterovirus 71 (EV71) is the major causative agent of severe hand, foot, and mouth disease, which affects millions of young children in the Asia-Pacific region annually. In this study, we engineered a novel EV71 virus-like particle (VLP) that lacks VP4 (therefore designated VLPΔVP4) and investigated its structure, antigenicity, and vaccine potential. The cryo-electron microscopy (cryo-EM) structure of VLPΔVP4was reconstructed to 3.71-Å resolution. Results from structural and biochemical analyses revealed that VLPΔVP4resembles the end product of the viral uncoating process, the 80S empty capsid. VLPΔVP4is able to elicit high-titer neutralizing antibodies and to fully protect mice against lethal viral challenge. Mechanistic studies showed that, at the cellular level, the anti-VLPΔVP4sera exert neutralization effects at both pre- and postattachment stages by inhibiting both virus attachment and internalization, and at the molecular level, the antisera can block multiple interactions between EV71 and its key receptors. Our study gives a better understanding of EV71 capsid assembly and provides important information for the design and development of new-generation vaccines for EV71, and perhaps for other enteroviruses, as well.IMPORTANCEEnterovirus 71 (EV71) infection may lead to severe hand, foot, and mouth disease, with significant morbidity and mortality. Knowledge regarding EV71 particle assembly remains limited. Here, we report the generation and characterization of a novel EV71 virus-like particle that lacks the VP4 capsid subunit protein. This particle, termed VLPΔVP4, structurally mimics the 80S empty capsid, which is the end stage of EV71 uncoating. We further show that VLPΔVP4exhibits desirable immunogenicity and protective efficacy in proof-of-concept studies. In addition, the inhibitory mechanisms of the VLPΔVP4-induced antibodies are unraveled at both the cellular and molecular levels. Our work provides the first evidence of picornaviral particle assembly in the complete absence of VP4 and identifies VLPΔVP4as an improved EV71 vaccine candidate with desirable traits. These findings not only enhance our understanding of particle assembly and uncoating of picornaviruses, but also provide important information for structure-guided vaccine design for EV71 and other enteroviruses.

scholarly journals Tyrosinase from mushroom Agaricus bisporus as an inhibitor of the Hepatitis C virus

2020 ◽  
Author(s):  
David Lopez-Tejedor ◽  
Rafael Clavería-Gimeno ◽  
Adrian Velazquez-Campoy ◽  
Olga Abian ◽  
Jose M. Palomo
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Agaricus Bisporus ◽  
Catalytic Mechanism ◽  
Low Cost ◽  
Inhibition Mechanism ◽  
System A ◽  
Viral Proteases ◽  
Hepatitis C Virus Proteins

AbstractTyrosinases from both a commercial semi-purified Agaricus bisporus protein extract and directly isolated from white mushroom have been demonstrated to show antiviral activity against the Hepatitis C virus for the first time. The well-known tyrosinase from A. bisporus (TyrAB) of 45kDa and a newly discovered 50-kDa isoform from this tyrosinase (Tyr50kDa) have been tested. Cell toxicity and antiviral activity of tyrosinases in cultured Huh 5-2 liver tumor cells transfected with a replicon system (a plasmid that includes all non-structural Hepatitis C virus proteins and replicates autonomously) was determined. Native TyrAB was able to inhibit the replication of the hepatitis C virus without inducing toxicity in liver cells. In addition, the post-translational isoform of Tyr50kDa showed higher antiviral capacity than the former (up to 10 times greater), , also exhibiting 10 times higher activity than the commercial drug Ribavirin®. This antiviral activity was directly proportional to the enzymatic activity of tyrosinases, since no antiviral capacity was observed for the inactive enzymes. The tyrosinases could represent a new antiviral inhibition mechanism through a catalytic mechanism of selective hydroxylation of key role tyrosine residues in viral proteases. The tyrosinases directly extracted from fresh mushroom (containing both tyrosinases) showed similar antiviral activity and, therefore, might provide low-cost drugs for the treatment of hepatitis C.

scholarly journals Lucidone Suppresses Hepatitis C Virus Replication by Nrf2-Mediated Heme Oxygenase-1 Induction

2012 ◽  
Vol 57 (3) ◽  
pp. 1180-1191 ◽  
Author(s):  
Wei-Chun Chen ◽  
Sheng-Yang Wang ◽  
Chien-Chih Chiu ◽  
Chin-Kai Tseng ◽  
Chun-Kuang Lin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Heme Oxygenase ◽  
Interferon Response ◽  
Hcv Rna ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Content Type ◽  
Ns5b Polymerase Inhibitor ◽  
High Concentrations

ABSTRACTUpon screening of plant-derived natural products against hepatitis C virus (HCV) in the replicon system, we demonstrate that lucidone, a phytocompound, isolated from the fruits ofLindera erythrocarpaMakino, significantly suppressed HCV RNA levels with 50% effective concentrations of 15 ± 0.5 μM and 20 ± 1.1 μM in HCV replicon and JFH-1 infectious assays, respectively. There was no significant cytotoxicity observed at high concentrations, with a 50% cytotoxic concentration of 620 ± 5 μM. In addition, lucidone significantly induced heme oxygenase-1 (HO-1) production and led to the increase of its product biliverdin for inducing antiviral interferon response and inhibiting HCV NS3/4A protease activity. Conversely, the anti-HCV activity of lucidone was abrogated by blocking HO-1 activity or silencing gene expression of HO-1 or NF-E2-related factor 2 (Nrf2) in the presence of lucidone, indicating that the anti-HCV action of lucidone was due to the stimulation of Nrf-2-mediated HO-1 expression. Moreover, the combination of lucidone and alpha interferon, the protease inhibitor telaprevir, the NS5A inhibitor BMS-790052, or the NS5B polymerase inhibitor PSI-7977, synergistically suppressed HCV RNA replication. These findings suggest that lucidone could be a potential lead or supplement for the development of new anti-HCV agent in the future.

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