November 2021
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60 Reads
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196 Citations
Journal of Medical Virology
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November 2021
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60 Reads
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196 Citations
Journal of Medical Virology
August 2021
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132 Reads
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79 Citations
Cell & Bioscience
Background As the COVID-19 pandemic rages on, the new SARS-CoV-2 variants have emerged in the different regions of the world. These newly emerged variants have mutations in their spike (S) protein that may confer resistance to vaccine-elicited immunity and existing neutralizing antibody therapeutics. Therefore, there is still an urgent need of safe, effective, and affordable agents for prevention/treatment of SARS-CoV-2 and its variant infection. Results We demonstrated that green tea beverage (GTB) or its major ingredient, epigallocatechin gallate (EGCG), were highly effective in inhibiting infection of live SARS-CoV-2 and human coronavirus (HCoV OC43). In addition, infection of the pseudoviruses with spikes of the new variants (UK-B.1.1.7, SA-B.1.351, and CA-B.1.429) was efficiently blocked by GTB or EGCG. Among the 4 active green tea catechins at noncytotoxic doses, EGCG was the most potent in the action against the viruses. The highest inhibitory activity was observed when the viruses or the cells were pre-incubated with EGCG prior to the infection. Mechanistic studies revealed that EGCG blocked infection at the entry step through interfering with the engagement of the receptor binding domain (RBD) of the viral spikes to angiotensin-converting enzyme 2 (ACE2) receptor of the host cells. Conclusions These data support further clinical evaluation and development of EGCG as a novel, safe, and cost-effective natural product for prevention/treatment of SARS-CoV-2 transmission and infection.
July 2021
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82 Reads
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17 Citations
Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide, resulting in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV vaccine is effective to prevent new HBV infection but does not offer therapeutic benefit to hepatitis B patients. Neither are current antiviral drugs curative of chronic hepatitis B. A more thorough understanding of HBV infection and replication holds a great promise for identification of novel antiviral drugs and design of optimal strategies towards the ultimate elimination of chronic hepatitis B. Recently, we have developed a robust HBV cell culture system and discovered that human apolipoprotein E (apoE) is enriched on the HBV envelope and promotes HBV infection and production. In the present study, we have determined the role of the low-density lipoprotein receptor (LDLR) in HBV infection. A LDLR-blocking monoclonal antibody potently inhibited HBV infection in HepG2 cells expressing the sodium taurocholate cotransporting polypeptide (NTCP) as well as in primary human hepatocytes. More importantly, small interfering RNAs (siRNAs)-mediated knockdown of LDLR expression and the CRISPR/Cas9-induced knockout of the LDLR gene markedly reduced HBV infection. A recombinant LDLR protein could block heparin-mediated apoE pulldown, suggesting that LDLR may act as an HBV cell attachment receptor via binding to the HBV-associated apoE. Collectively, these findings demonstrate that LDLR plays an important role in HBV infection probably by serving as a virus attachment receptor.
May 2021
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208 Reads
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23 Citations
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino-acid fragment of the 1,273-amino-acid S-protein protomer. The RBD is the primary SARS-CoV-2 neutralizing epitope and a critical target of any SARS-CoV-2 vaccine. Here, we show that this RBD conjugated to each of two carrier proteins elicited more potent neutralizing responses in immunized rodents than did a similarly conjugated proline-stabilized S-protein ectodomain. Nonetheless, the native RBD is expressed inefficiently, limiting its usefulness as a vaccine antigen. However, we show that an RBD engineered with four novel glycosylation sites (gRBD) is expressed markedly more efficiently and generates a more potent neutralizing responses as a DNA vaccine antigen than the wild-type RBD or the full-length S protein, especially when fused to multivalent carriers, such as a Helicobacter pylori ferritin 24-mer. Further, gRBD is more immunogenic than the wild-type RBD when administered as a subunit protein vaccine. Our data suggest that multivalent gRBD antigens can reduce costs and doses, and improve the immunogenicity, of all major classes of SARS-CoV-2 vaccines. IMPORTANCE All available vaccines for coronavirus disease 2019 (COVID-19) express or deliver the full-length SARS-CoV-2 spike (S) protein. We show that this antigen is not optimal, consistent with observations that the vast majority of the neutralizing response to the virus is focused on the S-protein receptor-binding domain (RBD). However, this RBD is not expressed well as an independent domain, especially when expressed as a fusion protein with a multivalent scaffold. We therefore engineered a more highly expressed form of the SARS-CoV-2 RBD by introducing four glycosylation sites into a face of the RBD normally occluded in the full S protein. We show that this engineered protein, gRBD, is more immunogenic than the wild-type RBD or the full-length S protein in both genetic and protein-delivered vaccines.
March 2021
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157 Reads
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4 Citations
As the COVID-19 pandemic rages on, the new SARS-CoV-2 variants have emerged in the different regions of the world. These newly emerged variants have mutations in their spike (S) protein that may confer resistance to vaccine-elicited immunity and existing neutralizing antibody therapeutics. Therefore, there is still an urgent need of safe, effective, and affordable agents for prevention/treatment of SARS-CoV-2 and its variant infection. Here, we demonstrated that green tea beverage (GTB) or its major ingredient, epigallocatechin gallate (EGCG), were highly effective in inhibiting infection of live SARS-CoV-2 and human coronavirus (HCoV OC43). In addition, infection of the pseudoviruses with spikes of the new variants (UK-B.1.1.7, SA-B.1.351, and CA-B.1.429) was efficiently blocked by GTB or EGCG. Among the 4 active green tea catechins at noncytotoxic doses, EGCG was the most potent in the action against the viruses. The highest inhibitory activity was observed when the viruses or the cells were pre-incubated with EGCG prior to the infection. Mechanistic studies revealed that EGCG blocked infection at the entry step through interfering with the engagement of the receptor binding domain (RBD) of the viral spikes to angiotensin-converting enzyme 2 (ACE2) receptor of the host cells. These data support further clinical evaluation and development of EGCG as a novel, safe, and cost-effective natural product for prevention/treatment of SARS-CoV-2 transmission and infection.
November 2020
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118 Reads
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5 Citations
The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates viral entry into cells expressing the angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of the 1273-amino acid S-protein protomer. The RBD is the primary SARS-CoV-2 neutralizing epitope and a critical target of any SARS-CoV-2 vaccine. Here we show that this RBD conjugated to each of two carrier proteins elicited more potent neutralizing responses in immunized rodents than did a similarly conjugated proline-stabilized S-protein ectodomain. Nonetheless, the native RBD expresses inefficiently, limiting its usefulness as a vaccine antigen. However, we show that an RBD engineered with four novel glycosylation sites (gRBD) expresses markedly more efficiently, and generates a more potent neutralizing responses as a DNA vaccine antigen, than the wild-type RBD or the full-length S protein, especially when fused to multivalent carriers such as an H. pylori ferritin 24-mer. Further, gRBD is more immunogenic than the wild-type RBD when administered as a subunit protein vaccine. Our data suggest that multivalent gRBD antigens can reduce costs and doses, and improve the immunogenicity, of all major classes of SARS-CoV-2 vaccines.
April 2020
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597 Reads
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87 Citations
The SARS-coronavirus 2 (SARS-CoV-2) spike (S) protein mediates entry of SARS-CoV-2 into cells expressing the angiotensin-converting enzyme 2 (ACE2). The S protein engages ACE2 through its receptor-binding domain (RBD), an independently folded 197-amino acid fragment of the 1273-amino acid S-protein protomer. Antibodies to the RBD domain of SARS-CoV (SARS-CoV-1), a closely related coronavirus which emerged in 2002-2003, have been shown to potently neutralize SARS-CoV-1 S-protein-mediated entry, and the presence of anti-RBD antibodies correlates with neutralization in SARS-CoV-2 convalescent sera. Here we show that immunization with the SARS-CoV-2 RBD elicits a robust neutralizing antibody response in rodents, comparable to 100 μg/ml of ACE2-Ig, a potent SARS-CoV-2 entry inhibitor. Importantly, anti-sera from immunized animals did not mediate antibody-dependent enhancement (ADE) of S-protein-mediated entry under conditions in which Zika virus ADE was readily observed. These data suggest that an RBD-based vaccine for SARS-CoV-2 could be safe and effective.
January 2020
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76 Reads
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88 Citations
Journal of Medical Virology
Emerging viral infections continue to pose a major threat to global public health. In 1997, a highly pathogenic avian influenza A (H5N1) virus was found to directly spread from poultry to humans unlike previously reported transmission routs of human‐to‐human and livestock‐to‐human, stirring a grave concern for a possible influenza pandemic. This article is protected by copyright. All rights reserved.
January 2020
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183 Reads
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104 Citations
SSRN Electronic Journal
October 2019
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27 Reads
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26 Citations
Virology
Zika virus (ZIKV) nonstructural protein 5 (NS5) is a multifunctional protein possessing methyltransferase and RNA-dependent RNA polymerase activities. In the present study, we have carried out an extensive mutagenesis analysis to determine the importance of nuclear localization sequences (NLS) of NS5 in its nuclear accumulation and ZIKV replication. Deletion mutagenesis analysis demonstrated that the bipartite NLS consisting of importin β1 (βNLS) and importin α/β-recognized NLS (α/βNLS) is required for NS5 nuclear accumulation. Deletion of βNLS, α/βNLS, or both as well as R393A and R393N mutations severely impaired NS5 nuclear import and consequently conferred NS5 degradation. The R393A and R393N mutations also ablated viral RNA replication and virus production. Treatment of ZIKV-infected cells with importin α/β-NS5 interaction inhibitors ivermectin or 4-HPR resulted in a rapid degradation of NS5 similar to the R393 A/N mutations. Collectively, these findings suggest that NS5 nuclear accumulation protects NS5 from cytoplasmic degradation and therefore is required for viral RNA replication.
... Using the viral hemagglutinin protein as a target, EGCG, a polyphenol present in green tea, was demonstrated to prevent influenza A and B virus entry into host cells [66]. It has also shown inhibitory effects on viral replication and reduced virus-induced inflammation [66]. ...
August 2021
Cell & Bioscience
... COVID-19 caused by SARS-CoV-2 infection has been raging worldwide since January 2020, bringing major challenges to public health and medical communities around the world. 1 Although the pathogenicity of the Omicron variant is considered to be significantly attenuated, the COVID-19 pandemic remains a worldwide public health crisis. 2,3 Several studies revealed that the incidence of COVID-19 was higher in schizophrenia patients than in those without psychiatric diagnoses. 4,5 Schizophrenia (SCZ) is a chronic, complex and disabling psychiatric disorder that is caused by genetic and/ or environmental disruption of brain development. ...
November 2021
Journal of Medical Virology
... Interestingly, a member of the low-density lipoprotein receptor (LDL-R) family, the low-density lipoprotein receptor-related protein 1 (Lrp1) was recently identified as a critical host entry factor for Rift Valley fever virus (RVFV) 8,9 and Oropouche orthobunyavirus (OROV) 10 , two members of the Bunyavirales order. In addition, other members of the LDL-R family, i.e., the very-low-density lipoprotein receptor (VLDL-R) and the apolipoprotein E receptor 2 (apoER2) were also recently identified as host factors for cell entry of alphaviruses 11 , while LDL-R was identified as host entry factor for hepatitis C virus (HCV) [12][13][14] , hepatitis B virus (HBV) 15 , Japanese encephalitis virus (JEV) 16 . Finally, several members of the LDL-R family are involved as receptors in vesicular stomatitis virus (VSV) entry 17,18 , suggesting that lipid transfer receptors might be used by different viral families. ...
July 2021
... Rat models have been used to study the pathophysiology of human diseases. In this regard, the ACE2 protein of rats interacts weakly with spike protein of SARS-CoV, possibly because rat ACE2 contains glycosylation sites that lead to steric interference with SARS-CoV binding [64][65][66]. Understanding this mechanism can help in the search for therapeutic alternatives. ...
May 2021
... Epigallocatechin-3-gallat (EGCG, Fig. 1A), a major component of the green tea extract, is currently in the limelight, as it shows pronounced inhibitory activity against various types of viruses, especially with positive-sense single-stranded RNA genomes [1]. Discussions on EGCG applicability for SARS-CoV-2 treatment or prevention are mostly grounded by the results of lentiviral systembased assays [2]. Direct evidence for EGCG activity against SARS-CoV-2 is limited [3], and detailed experiments with the live virus and various treatment schemes are much needed. ...
March 2021
... All currently known platforms used for vaccine development have been used to produce vaccines against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) including inactivated virus [1,2], recombinant proteins and synthetic peptides [3][4][5], vector vaccines [6,7], DNA-based constructs [8,9], and RNA-based constructs [10,11]. Each has its advantages and disadvantages. ...
November 2020
... The animal model used in the present study to demonstrate the nontoxicity of the vaccine candidate FINLAY-FR-02 in SD rats is a well-characterized model for vaccine toxicological studies and has been used previously in preclinical studies on SARS-CoV-2 vaccines [21][22][23][24] . ...
January 2020
SSRN Electronic Journal
... For the design of the first immunogen, the sequence encoding the receptor-binding domain (RBD) of SARS-CoV-2 spike protein published in GenBank (320 V-542 N, MN908947) was used. For SARS-CoV-2, the RBD protein is a good antigen candidate because this relatively small protein is the primary target of neutralizing antibodies [38][39][40][41][42][43][44]. ...
April 2020
... The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was a public health event with global effects [1,2]. As of October 25, 2023, the World Health Organization has reported over 770 million cases of SARS-CoV-2 infection, resulting in nearly seven million deaths [3]. ...
January 2020
Journal of Medical Virology
... Considering the accepted role of MTs in innate immunity and infection [92,[109][110][111][112], their essential roles in intracellular trafficking and cell morphology (reviewed in [113]), the involvement of the ZIKV NS5 protein in virus replication and evasion from the interferon (IFN)-associated immune response, and its association with the centrosome or microtubule (MT) organized center (MTOC) during mitosis and cell division [95,[114][115][116], we aimed to study the effect of the ZIKV NS5 protein on MTs to ascertain potential interplay at this level. Our results indicate that the ZIKV NS5 protein mainly accumulates in nuclear structures, as previously reported [64,65,117,118], and promotes the acetylation of MTs that aberrantly reorganize in nested-like structures organized at the cell periphery. Similarly, we observed that the p62 protein, a marker of autophagy flux [97][98][99][100][101][102][103], accumulated in cells overexpressing the ZIKV NS5 protein. ...
October 2019
Virology