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1.
Cell Rep ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31956073

RESUMO

We perform a CRISPR-Cas9 genome-wide screen in glioblastoma stem cells and identify integrin αvß5 as an internalization factor for Zika virus (ZIKV). Expression of αvß5 is correlated with ZIKV susceptibility in various cells and tropism in developing human cerebral cortex. A blocking antibody against integrin αvß5, but not αvß3, efficiently inhibits ZIKV infection. ZIKV binds to cells but fails to internalize when treated with integrin αvß5-blocking antibody. αvß5 directly binds to ZIKV virions and activates focal adhesion kinase, which is required for ZIKV infection. Finally, αvß5 blocking antibody or two inhibitors, SB273005 and cilengitide, reduces ZIKV infection and alleviates ZIKV-induced pathology in human neural stem cells and in mouse brain. Altogether, our findings identify integrin αvß5 as an internalization factor for ZIKV, providing a promising therapeutic target, as well as two drug candidates for prophylactic use or treatments for ZIKV infections.

2.
Virulence ; 11(1): 113-131, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31957543

RESUMO

Zika virus (ZIKV) infection in the human central nervous system (CNS) causes Guillain-Barre syndrome, cerebellum deformity, and other diseases. Astrocytes are immune response cells in the CNS and an important component of the blood-brain barrier. Consequently, any damage to astrocytes facilitates the spread of ZIKV in the CNS. Connective tissue growth factor/Nephroblastoma overexpressed gene family 1 (CCN1), an important inflammatory factor secreted by astrocytes, is reported to regulate innate immunity and viral infection. However, the mechanism by which astrocyte viral infection affects CCN1 expression remains undefined. In this study, we demonstrate that ZIKV infection up-regulates CCN1 expression in astrocytes, thus promoting intracellular viral replication. Other studies revealed that the cAMP response element (CRE) in the CCN1 promoter is activated by the ZIKV NS3 protein. The cAMP-responsive element-binding protein (CREB), a transacting factor of the CRE, is also activated by NS3 or ZIKV. Furthermore,a specific inhibitor of CREB, i.e. SGC-CBP30, reduced ZIKV-induced CCN1 up-regulation and ZIKV replication. Moreover, co-immunoprecipitation, overexpression, and knockdown studies confirmed that the interaction between NS3 and the regulatory domain of CaMKIIα could activate the CREB pathway, thus resulting in the up-regulation of CCN1 expression and enhancement of virus replication. In conclusion, the findings of our investigations on the NS3-CaMKIIα-CREB-CCN1 pathway provide a foundation for understanding the infection mechanism of ZIKV in the CNS.

3.
Bioorg Med Chem Lett ; 30(4): 126906, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31902708

RESUMO

The prevalence of Zika virus (ZIKV) has become widespread in recent years. ZIKV infection is associated with severe congenital CNS malformations in both newborns and adults. However, neither vaccines nor therapeutics are available to control ZIKV infection until now. We started by hit screening our in-house small molecule library, then designed, synthesized, and evaluated a new class of 1, 4-bibenzylsubstituted piperazine derivatives for their cytopathic effect (CPE) protection effect in a ZIKV-infected Vero E6 cellular assay. A preliminary structure-activity relationship study identified five novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile analogs with obvious CPE reduction effects against ZIKV at micromolar concentrations. Moreover, compound 3p exerted a significant antiviral effect on both Zika RNA replication and virus protein expression in a dose-dependent manner at low micromolar concentrations. This study demonstrated the potential of a novel 4-amino-2-(4-benzylpiperazin-1-yl)methylbenzonitrile scaffold for the development of anti-ZIKV candidates.

4.
Eur J Pediatr ; 179(2): 235-242, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912233

RESUMO

Immunizing pregnant women to protect the mother, fetus and infant from infection has increasingly been used over the last decade. Protection against infectious diseases in neonates is mainly provided by maternal antibodies transferred from mother to infant during pregnancy through transplacental transport or after delivery via breastfeeding. Both the transplacental- and breast milk-derived maternal antibodies function as the primary source of protection against infectious diseases in neonates during the first vulnerable weeks of life. During recent infectious disease outbreaks (influenza, pertussis, Zika…) and for other infectious diseases (CMV, GBS…), pregnant women are increasingly identified as an important target for vaccination. For some of these diseases, vaccines are already on the market, and recommended during pregnancy. For others, vaccines are currently under development; furthermore, some are even specifically designed to be administered during pregnancy.Conclusion: This review article provides an overview on the rationale and main mechanism of the maternal vaccination strategy and gives a summary about the current and possible future recommendations for maternal vaccination.What is Known:• Maternal vaccination has a far-reaching potential in the protection of both women and offspring.• Currently, tetanus, pertussis and influenza vaccination during pregnancy is recommended in some countries. Several new vaccines specifically designed for use in pregnancy are currently under development.What is New:• Review providing a timely overview of the rationale and main mechanisms of the maternal vaccination strategy• Up-to-date summary of the current and possible future recommendations for maternal vaccination.

5.
J Biomed Sci ; 27(1): 27, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959174

RESUMO

Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an arbovirus that can cause congenital abnormalities and is sexually transmissible. A series of outbreaks accompanied by unexpected severe clinical complications have captured medical attention to further characterize the clinical features of congenital ZIKV syndrome and its underlying pathophysiological mechanisms. Endoplasmic reticulum (ER) and ER-related proteins are essential in ZIKV genome replication. This review highlights the subcellular localization of ZIKV to the ER and ZIKV modulation on the architecture of the ER. This review also discusses ZIKV interaction with ER proteins such as signal peptidase complex subunit 1 (SPCS1), ER membrane complex (EMC) subunits, and ER translocon for viral replication. Furthermore, the review covers several important resulting effects of ZIKV infection to the ER and cellular processes including ER stress, reticulophagy, and paraptosis-like death. Pharmacological targeting of ZIKV-affected ER-resident proteins and ER-associated components demonstrate promising signs of combating ZIKV infection and rescuing host organisms from severe neurologic sequelae.

6.
Viruses ; 12(1)2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31947825

RESUMO

Zika virus (ZIKV) emerged in the Americas in 2015, presenting unique challenges to public health. Unlike other arboviruses of the Flaviviridae family, it is transmissible by sexual contact, which facilitates the spread of the virus into new geographic areas. Additionally, ZIKV can be transmitted from mother to fetus, causing microcephaly and other severe developmental abnormalities. Reliable and easy-to-work-with clones of ZIKV expressing heterologous genes will significantly facilitate studies aimed at understanding the virus pathogenesis and tissue tropism. Here, we developed and characterized two novel approaches for expression of heterologous genes of interest in the context of full-length ZIKV genome and compared them to two previously published strategies for ZIKV-mediated gene expression. We demonstrated that among the four tested viruses expressing nLuc gene, the virus constructed using a newly developed approach of partial capsid gene duplication (PCGD) attained the highest titer in Vero cells and resulted in the highest level of nLuc expression. Suitability of the PCGD approach for expression of different genes of interest was validated by replacing nLuc sequence with that of eGFP gene. The generated constructs were further characterized in cell culture. Potential applications of ZIKV clones stably expressing heterologous genes include development of detection assays, antivirals, therapeutics, live imaging systems, and vaccines.

7.
Cells ; 9(1)2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31947958

RESUMO

To date, no safe vaccine or antivirals for Zika virus (ZIKV) infection have been found. The pathogenesis of severe Zika, where host and viral factors participate, remains unclear. For the control of Zika, it is important to understand how ZIKV interacts with different host cells. Knowledge of the targeted cellular pathways which allow ZIKV to productively replicate and/or establish prolonged viral persistence contributes to novel vaccines and therapies. Monocytes and endothelial vascular cells are the main ZIKV targets. During the infection process, cells are capable of releasing extracellular vesicles (EVs). EVs are mediators of intercellular communication. We found that mosquito EVs released from ZIKV-infected (C6/36) cells carry viral RNA and ZIKV-E protein and are able to infect and activate naïve mosquito and mammalian cells. ZIKV C6/36 EVs promote the differentiation of naïve monocytes and induce a pro-inflammatory state with tumor necrosis factor-alpha (TNF-α) mRNA expression. ZIKV C6/36 EVs participate in endothelial vascular cell damage by inducing coagulation (TF) and inflammation (PAR-1) receptors at the endothelial surface of the cell membranes and promote a pro-inflammatory state with increased endothelial permeability. These data suggest that ZIKV C6/36 EVs may contribute to the pathogenesis of ZIKV infection in human hosts.

8.
J Theor Biol ; : 110161, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31953137

RESUMO

Effective public health measures must balance potentially conflicting demands from populations they serve. In the case of infectious disease risks from mosquito-borne infections, such as Zika virus, public concern about the pathogen may be counterbalanced by public concern about environmental contamination from chemical agents used for vector control. Here we introduce a generic framework for modeling how the spread of an infectious pathogen might lead to varying public perceptions, and therefore tolerance, of both disease risk and pesticide use. We consider how these dynamics might impact the spread of a vector-borne disease. We tailor and parameterize our model for direct application to Zika virus as spread by Aedes aegypti mosquitoes, though the framework itself has broad applicability to any arboviral infection. We demonstrate how public risk perception of both disease and pesticides may drastically impact the spread of a mosquito-borne disease in a susceptible population. We conclude that models hoping to inform public health decision making about how best to mitigate arboviral disease risks should explicitly consider the potential public demand for, or rejection of, chemical control of mosquito populations.

9.
PLoS One ; 15(1): e0227058, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910225

RESUMO

Nanotrap® (NT) particles are hydrogel microspheres developed for target analyte separation and discovery applications. NT particles consist of cross-linked N-isopropylacrylamide (NIPAm) copolymers that are functionalized with a variety of chemical affinity baits to enable broad-spectrum collection and retention of target proteins, nucleic acids, and pathogens. NT particles have been previously shown to capture and enrich arboviruses including Rift Valley fever and Venezuelan equine encephalitis viruses. Yet, there is still a need to enhance the detection ability for other re-emerging viruses such as Zika (ZIKV), chikungunya (CHIKV), and dengue (DENV) viruses. In this study, we exploited NT particles with different affinity baits, including cibacron blue, acrylic acid, and reactive red 120, to evaluate their capturing and enrichment capability for ZIKV, DENV and CHIKV in human fluids. Our results demonstrate that CN1030, a NT particle conjugated with reactive red 120, can recover between 8-16-fold greater genomic copies of ZIKV, CHIKV and DENV in virus spiked urine samples via RT-qPCR, superior to the other chemical baits. Also, we observed that CN1030 simultaneously enriched ZIKV, CHIKV and DENV in co-infection-based settings and could stabilize ZIKV, but not CHIKV infectivity in saliva spiked samples. CN1030 enriched viral detection at various viral concentrations, with significant enhancement observed at viral titers as low as 100 PFU/mL for ZIKV and 10 PFU/mL for CHIKV. The detection of ZIKV was further enhanced with NT particles by processing of larger volume urine samples. Furthermore, we developed a magnetic NT particle, CN3080, based on the same backbone of CN1030, and demonstrated that CN3080 could also capture and enrich ZIKV and CHIKV in a dose-dependent manner. Finally, in silico docking predictions support that the affinity between reactive red 120 and ZIKV or CHIKV envelope proteins appeared to be greater than acrylic acid. Overall, our data show that NT particles along with reactive red 120 can be utilized as a pre-processing technology for enhancement of detecting febrile-illness causing viruses.

10.
PLoS Negl Trop Dis ; 14(1): e0007970, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31961867

RESUMO

BACKGROUND: Arboviruses transmitted by day-biting Aedes mosquitoes are a major public health concern. With the challenges inherent in arbovirus vaccine and therapeutics development, vector control and bite prevention strategies are among the limited options available for immediate intervention. Bite prevention through personal protective technologies (PPT), such as topical mosquito repellents or repellent-impregnated clothing, may help to decrease biting rates and, therefore, the risk of disease in groups most susceptible to adverse outcomes from Zika virus. However, achieving high uptake and compliance with PPT can be challenging. METHODOLOGY/PRINCIPAL FINDINGS: To gain an insight into the knowledge and concerns of pregnant women surrounding Zika and their opinions regarding PPT, particularly repellent clothing, a focus group study was carried out with pregnant women, women of reproductive age, and semi-structured interviews with their male partners in two cities in Colombia. The discussions revealed shortfalls in basic knowledge of Zika virus, with several pregnant participants reporting being unaware of the potential for Zika-related congenital malformations. Although participants generally considered Zika to be a significant personal threat, most rated it as less of a concern than dengue or diarrheal diseases. Overall, repellent clothing and other forms of PPT were viewed as effective, although some participants expressed concerns over the high costs of repellents, and safety fears of regular contact with repellent chemicals, which they perceived as potentially harmful. Plant-derived repellents were considered to be safer than synthetic chemical repellents. Discussions also highlighted that health centers were the preferred source of information on bite-reduction. CONCLUSIONS/SIGNIFICANCE: Achieving high uptake and compliance with PPT in populations most at risk of adverse outcomes from Zika infection requires engaging key users in open dialogue to identify and address any practical issues regarding PPT use, and concerns over safety. The findings presented here suggest that educational campaigns should strongly emphasize the risks associated with Zika during pregnancy, and discuss safety profiles of approved synthetic repellents and the availability of EPA-approved plant-based repellents. In addition, the economic and political context should be a major consideration when evaluating personal mosquito-repellent strategies.

11.
Infect Genet Evol ; : 104199, 2020 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-31962160

RESUMO

Zika virus (ZIKV) is an RNA virus that has spread through mosquito sting. Currently, no vaccine and antiviral medication available so far against ZIKV. Therefore, it has fostered a study to design MEBP vaccine enabling effective prevention against the ZIKV infection. In this study combination of immuno-informatics and molecular docking approach was used to constitute a MEBP vaccine. The ZIKV proteome was used for prediction of B-cell, T-cell (HTL & CTL) and IFN-γ epitopes. After prediction, highly antigenic and overlapping epitopes have been shortlisted which includes 14 CTL and 11 HTL epitopes that have been linked to the final peptide through AAY and GPGPG linkers respectively. An adjuvant at the N-end of the vaccine was added to improve the immunogenicity of the vaccine through the EAAAK linker. The final construct constitutes 435 amino acids after the addition of linkers and adjuvant. The existence of B-cell and IFN-γ epitopes affirms the humoral and cell-mediated immune responses acquired by the construct. Allergenicity, antigenicity and different physiochemical attributes of the vaccine were evaluated to assure its safety and immunogenicity profile. In fact, the construct was antigenic and non-allergenic. Docking was performed among vaccine and TLR-3 to evaluate the binding affinity and the molecular interaction. Finally, the construct was subjected to In silico cloning to confers the authenticity of its expression efficiency. However, the proposed construct need to be validate experimentally to ensure its safety and immunogenic profile.

12.
G3 (Bethesda) ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964684

RESUMO

Aedes albopictus mosquitoes are important vectors for a number of human pathogens including the Zika, dengue, and chikungunya viruses. Capable of displacing Aedes aegypti populations, this mosquito adapts to cooler environments which increases its geographical range and transmission potential. There are limited control strategies for Aedes albopictus mosquitoes which is likely attributed to the lack of comprehensive biological studies on this emerging vector. To fill this void, here using RNAseq we characterized Aedes albopictus mRNA expression profiles at 34 distinct time points throughout development providing the first high-resolution comprehensive view of the developmental transcriptome of this worldwide human disease vector. This enabled us to identify several patterns of shared gene expression among tissues as well as sex-specific expression patterns. To illuminate the similarities and differences with Aedes aegypti, a related human disease vector, we also performed a comparative analysis between the two developmental transcriptomes, identifying life stages where the two species exhibit similar and distinct gene expression patterns. These findings provide insights into the similarities and differences between Aedes albopictus and Aedes aegypti mosquito biology. In summary, the results generated from this study should form the basis for future investigations on the biology of Aedes albopictus and provide a gold mine resource for the development of transgene-based vector control strategies.

13.
Emerg Infect Dis ; 26(2): 315-319, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31967538

RESUMO

We queried hospital patients about international travel in the previous 30 days to assess potential importation of emerging infections. We used 12 months of deidentified data to analyze patient demographics, travel destinations, and diagnoses for exposure to Zika virus. Our approach could be used to analyze potential infectious disease exposures.

14.
ACS Infect Dis ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967789

RESUMO

Flaviviruses including Zika virus, Dengue virus, Japanese Encephalitis virus and Yellow Fever virus cause heavy burdens to public health around the world. No specific antiviral drug was available in clinic against these flavivirus infections. Heat-shock protein 70 (HSP70) has recently been proven to be a promising antiviral target against Zika virus and Dengue virus. Here, we report that, Apoptozole, a small molecule inhibitor of ATPase activity of HSP70 has broad-spectrum anti-flavivirus potential. The mode of action analysis revealed that Apoptozole acted at post-entry step. Transcriptome analysis revealed that genes related to cholesterol metabolism, fatty acid synthesis and innate immunity were differentially expressed after treatment of Apoptozole. In vivo data suggested Apoptozole exerted protection effects against ZIKV infection in mouse model by enhancing innate immune response, which suggested a novel anti-ZIKV mechanism of HSP70 inhibitors. Key words: Flavivirus, Antiviral, Apoptozole, Zika virus, Innate immunity.

15.
Eur Neurol ; : 1-8, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31968331

RESUMO

BACKGROUND: In 1947, Zika virus (ZIKV) was first discovered in Monkeys, in Zika Forest, in Uganda, Africa. Five years later, (1952) the first human Zika infection was detected in Nigeria, Africa. After this date, only sporadic cases happened, until the first 3 epidemics occurred, all outside Africa. The first epidemic was in Yap Island in 2007, the second in French Polynesia in 2013, and the third in 2015 in the northeast of Brazil, and then the spread to the Americas in 2015 and 2016. However, it was only after the epidemic in the northeast of Brazil, in the first half of 2015, that many babies were born with microcephaly in the second semester of that same year and in 2016. Until now, every year, some babies are still born with congenital ZIKV syndrome (CZVS). SUMMARY: The objective of this article is to describe infrequent and rarely discussed imaging (computed tomography and magnetic resonance imaging) findings of CZVS, in addition to those classically described such as a simplified gyral pattern, ventriculomegaly, corpus callosum dysgenesis, craniofacial disproportion, and redundant scalp, thus suggesting an increase in the spectrum of neurological findings related to the syndrome.

16.
Acta Neurol Belg ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970702

RESUMO

Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated polyradiculoneuropathy, often precipitated by an antecedent infection. An association of GBS with vector-borne viral infections has been suggested, with evidence for the involvement of Zika, Dengue, Chikungunya and West Nile virus (WNV). This prospective case-control study was conducted to identify vector-borne viral infections in GBS. Thirteen individuals newly diagnosed as GBS were enrolled. Disease severity, prognostic factors and nerve conduction patterns were assessed. Eleven individuals with non-infectious conditions requiring cerebrospinal fluid (CSF) analysis were included as controls. Plasma, CSF and urine specimens were evaluated via nucleic acid amplification assays aimed to detect a broad spectrum of viruses. WNV and Toscana virus (TOSV) IgM/IgG antibodies were screened using commercial immunofluorescence assays and confirmed via virus neutralization tests (VNT). Partial TOSV nucleocapsid and genotype 1 polymerase sequences were detected in CSF of a patient with normal pressure hydrocephalus. Two control subjects had VNT-confirmed TOSV IgM in plasma. VNT-confirmed WNV and TOSV IgG were detected in 15.4% and 61.5% of GBS patients, respectively. Variations in WNV IgG and TOSV IgM detection rates were not statistically significant among study cohorts. However, TOSV IgG was significantly more frequent in GBS patients. No difference was observed for disease form or prognostic scores for virus markers. Follow-up serological profiles were identical to the initial findings. We have identified TOSV as a potential precipitating agent in GBS, with some rare clinical presentations of symptomatic TOSV infections.

17.
Clin Exp Dermatol ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31916616

RESUMO

Skin disorders are frequent in travelers, but data vary according to different studies. Our objectives were to describe imported dermatoses in the Bordeaux Geosentinel prospective database. between August 2015 and March 2018. During the study period, 1,025 travelers were seen in the clinic, 201 of them with dermatoses. Patients with skin disorders were more likely to be > 60 (OR 1.88, 95% CI [1.22-2.89]), tourists (OR 3.04, 95% CI [2.03-4.55]), travelers to South America (OR 2.18, 95% CI [1.29-3.67]) and less likely to be seen in pre-travel encounters (OR 0.53, 95% CI [0.31-0.91]). Skin bacterial infections (19.4%) and Zika virus infections (18.4%) were the most common dermatoses. Dengue fever and bacterial skin infections were the leading causes of hospitalization. The contribution of tropical diseases among imported dermatoses remains important. Lack of pre-travel advice puts tourists at risk of significant diseases such as dengue fever, Zika or bacterial infections.

18.
Cell Host Microbe ; 27(1): 14-24, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31917957

RESUMO

Humoral immunity is an essential component of the protective immune response to flavivirus infection. Typically, primary infection generates a robust neutralizing antibody response that mediates viral control and protection. It is becoming increasingly apparent that secondary infection with a closely related flavivirus strain can result in immunological cross-reactivity; however, the consequences to infection outcome remain controversial. Since its introduction to Brazil in 2015, Zika virus (ZIKV) has caused an epidemic of fetal congenital malformations within the Americas. Because ZIKV is a mosquito-borne flavivirus with a high degree of sequence and structural homology to Dengue virus (DENV), the role of immunological cross-reactivity in ZIKV and DENV infections has become a great concern. In this review, we highlight contemporary findings that implicate a role for flavivirus antibodies in mediating protection, contributing to pathogenesis, and seeding the human placenta.

19.
J Biol Chem ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919100

RESUMO

The genus Flavivirus in the family Flaviviridae comprises many medically important viruses, such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV). The quest for therapeutic targets to combat flavivirus infections requires a better understanding of the kinetics of virus-host interactions during infections with native viral strains. However, this is precluded by limitations of current cell-based systems for monitoring flavivirus infection in living cells. In the present study, we report the construction of fluorescence activatable sensors to detect the activities of flavivirus NS2B-NS3 serine proteases in living cells. The system consists of GFP-based reporters that become fluorescent upon cleavage by recombinant DENV-2/ZIKV proteases in vitro. A version of this sensor containing the flavivirus internal NS3 cleavage site linker reported the highest fluorescence activation in stably transduced mammalian cells upon DENV-2/ZIKV infection. Moreover, the onset of fluorescence correlated with viral protease activity. A far-red version of this flavivirus sensor had the best signal-to-noise ratio in a fluorescent Dulbecco's plaque assay, leading to the construction of a multi-reporter platform combining the flavivirus sensor with reporter dyes for detection of chromatin condensation and cell death, enabling studies of viral plaque formation with single-cell resolution. Finally, the application of this platform enabled the study of cell-population kinetics of infection and cell death by DENV-2, ZIKV, and YFV. We anticipate that future studies of viral infection kinetics with this reporter system will enable basic investigations of virus-host interactions and facilitate future applications in antiviral drug research to manage flavivirus infections.

20.
J Biomol Struct Dyn ; : 1-13, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31920173

RESUMO

Zika virus (ZIKV), belongs to the flavivirus genus and Flaviviridae family that associated with serious diseased conditions like microcephaly and other neurological disorders (Guillan-Barré syndrome). As there is no vaccine or therapies available against ZIKV to date. Hence, it is an unmet need to find potential drug candidates and target sites against Zika virus infection. NS2B-NS3 protease making an attractive target for therapeutic intervention in ZIKV infections because of its critical role in hydrolysis of a single polyprotein encoded by Zika virus. Recently, there are some experimental evidence about the flavonoids as Zika virus NS2B-NS3 protease inhibitors. However, molecular interaction between protease complex and inhibitors at atomic levels has not been explored. Here, we have taken the experimentally validated thirty-eight flavonoids inhibitors against NS2B-NS3 protease to examine the molecular interaction using molecular docking and molecular dynamics simulations. We found out few flavonoids such as EGCG and its two derivatives, isoquercetin, rutin and sanggenon O showing interaction with catalytic triad (His51, Asp75, and Ser135) of the active site of NS2B-NS3 protease and found to be stable throughout the simulation. Therefore it is evident that interaction with the catalytic triad playing a vital role in the inhibition of the enzyme activity as a result inhibition of the virus propagation. However these compounds can be explored further for understanding the mechanism of action of these compounds targeting NS2B-NS3 protease for inhibition of Zika virus.

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