Francois Jean
Research Classification
Research Interests
Relevant Thesis-Based Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Research Options
Research Methodology
Recruitment
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Antiviral strategies and antiviral therapeutics
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Comparative phenotypic profiling and genomic analysis of circulating SARS-CoV-2 Variants of Concern
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Discovering broad-spectrum therapeutics for human viral diseases
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Discovering novel broad-spectrum antiviral agents from natural product libraries
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Unraveling the molecular mechanism of actions of newly discovered broad-spectrum antiviral molecules against human viruses using 2D and 3D organoids
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Discovery of human host factors required for human virus infection using CRISPR-Cas9 genome editing technology
- Identifying repurposable drug candidates for viral infection either tested alone or in combination using human organoid-based screening platforms with the goal of identifying synergistic drug combinations.
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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The four serotypes of dengue virus (DENV-1–4) are viruses of global concern. Although it is a key step in the lifecycle of these viruses, the host-mediated proteolytic maturation of the structural membrane precursor (prM) glycoprotein is an enigmatic molecular event. Maturation of prM is required for DENV infectivity. This proteolysis is thought to be mediated by human furin, a member of the proprotein convertase family of endoproteases that cleaves a wide variety of host cell molecules and is often hijacked by infectious agents to facilitate their lifecycle. DENV prM maturation is enigmatic for three reasons. First, a cleavage sequence that would be poorly processed by furin has been selected in all four serotypes, resulting in a large proportion of uncleaved immature prM on nascent virus particles. Second, it is unknown whether furin is the sole host enzyme responsible for cleaving prM. Third, while this event has been studied in the context of DENV-2, it is unknown whether the other three serotypes behave similarly with regard to prM maturation rate and its dependence on host furin. Research into these biological questions has been hindered by a lack of molecular tools to accurately quantify DENV-1–4 prM maturation.Here, we developed a novel adaptation of multiple reaction monitoring mass spectrometry (MRM-MS) that uses N-terminal acetyl (NTAc) labelling to differentially quantify cleaved M and uncleaved prM. We applied our NTAc-MRM methodology to determine the relative maturation rate of DENV-1–4 derived from cultured human cells and found significant differences among the serotypes. We also found that prM maturation of DENV-1 does not require active furin. Finally, we applied NTAc-MRM to quantify DENV-1–4 prM maturation in the presence of an adenovirus-expressed serine protease inhibitor (serpin), Spn4A, which stoichiometrically inhibits furin-like proteases. We found that the ER-retained form of Spn4A inhibited DENV-1–4 prM maturation, but a constitutively secreted form of Spn4A produced a robust inhibition of the DENV lifecycle, including intracellular vRNA synthesis, which cannot be explained solely in terms of prM maturation. We therefore hypothesize that host cellular targets of furin-like proteases play an important part in the DENV lifecycle.
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Cholesterol and lipid levels are maintained through tightly controlled and complex feedback mechanisms that involve regulation of major metabolic genes. Dysregulation of cellular or plasma lipid levels can lead to a wide range of pathologies, including hyperlipidemia, atherosclerosis and other disorders. A number of viruses, including important human viruses of the Flaviviridae family such as hepatitis C virus (HCV) and dengue virus (DENV), utilize and modulate host lipids to support their lifecycles, and the resulting changes in lipid metabolism may contribute to virus-associated pathologies. The overall aim of this thesis was to determine the role of key regulators of host lipid homeostasis, including microRNAs (miR-122, miR-24 and miR-223) and proprotein convertases (SKI-1/S1P and PCSK9) during viral infection and virus-associated disease.To address this aim, we first examined the molecular interplay between three circulating microRNAs known to act as regulators of lipid homeostasis. The data we present in Chapter 2 shows that specific signatures of the three microRNAs were associated with different treatment outcomes in patients with chronic hepatitis C (CHC), indicating that these microRNAs correlate with HCV infection. We then tested the hypothesis that enzymatic regulators of lipid metabolism could also indicate HCV infection, and in Chapter 3 we show that PCSK9 levels were significantly upregulated in patients who achieved a treatment-based viral cure but not in relapsers. These data indicate that changes in PCSK9 concentrations may have an important role in both HCV infection and in host lipid metabolism. In Chapter 4, we tested whether reducing the abundance of lipid droplets via inhibition of SKI-1/S1P with a small molecule PF-429242 suppresses DENV infection. The inhibitor blocked SKI-1/S1P-mediated accumulation of lipid droplets in hepatoma cells and reduced DENV infection, identifying SKI-1/S1P as a potential target for indirect-acting anti-DENV agents. This study on modulators of lipid metabolism during HCV and DENV infections provides new insights into the complex host-virus interactions that associate with virally-induced disease. We hope that our data lay the foundation for understanding disease pathogenesis and support the development of future strategies for Flaviviridae - associated diseases.
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The hijacking and manipulation of host cell biosynthetic pathways by human viruses are shared molecular events that are essential for the viral life cycle. Because of increasing evidence of the importance of human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in host secretory pathway functions, I hypothesized that this multifunctional enzyme could contribute to life cycles of two Flaviviridae members, hepatitis C virus (HCV) and dengue virus (DENV).The first aim of this project was to investigate whether GAPDH is a host factor that regulates the life cycle steps of HCV in human hepatoma Huh-7.5.1 cells. I used short interfering RNA (siRNA)-mediated silencing of GAPDH both pre- and post-HCV infection in Huh-7.5.1 cells to demonstrate that reducing GAPDH protein abundance inhibits primary HCV infection and production and/or release of infectious HCV virus particles. Exogenous expression of V5-tagged human GAPDH, pre- and post-infection, increases the viral infectivity of HCV-infected Huh-7.5.1 cell supernatants, suggesting a predominant role of GAPDH during the post-replication steps of the HCV life cycle. Finally, siRNA-mediated GAPDH suppression in human Huh-7.5.1 cells also significantly inhibited primary DENV-2 infection.In the second aim, I further investigated the diverse functions of GAPDH in human hepatoma cells by performing differential expression profiling of total cellular proteins by quantitative proteomics in two GAPDH knockdown Huh-7-derived cell lines (67D2 and 67b3) and the parental Huh-7 cell line. First, I successfully established GAPDH knockdown Huh-7-derived cell lines using short hairpin RNA (shRNA) lentivirus particles. Second, I demonstrated that the stable shRNA-mediated GAPDH silencing in Huh-7 cells inhibits primary HCV infection and the production of infectious HCV virus particles. Using a quantitative proteomics strategy based on triplex dimethyl labeling and nano-liquid chromatography-tandem mass spectrometry, I determined the cellular proteins deregulated in 67D2 and 67B3 cells. Bio-informatic analysis of the differentially expressed proteins revealed a robust compensatory effect in molecular functions associated with enzymatic activities and “acting binding” in response to the silencing of GAPDH in 67D2 and 67D3 cells.
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Over the past twenty years small endogenous non-coding RNAs known as microRNAs have emerged as potent regulators of gene expression during virus infection. During influenza A virus infection the role of miRNAs and their impact on the virus lifecycle is relatively unknown. With seasonal strains that can result in annual epidemics, to newly emerging subtypes that have the potential to cause a worldwide pandemic, influenza A remains a major threat to global human health. Here we aimed to determine the role miRNAs play in the host-pathogen interactions associated with varying pathogenesis during infection with different influenza A virus strains. In Chapter 2, we tested the hypothesis that human cellular miRNA expression would vary between a low pathogenic swine-origin H1N1 influenza A virus strain and a highly pathogenic avian-origin H7N7 influenza A virus strain. Utilizing high throughput microarray analysis, we identified differentially expressed miRNA and mRNA profiles during H1N1 and H7N7 influenza A infection and found strain specific expression patterns that were associated with specific cellular pathways. One of the miRNAs identified in Chapter 2 was miR-24 that targets the proprotein convertase furin, which is responsible for cleaving the hemagglutinin glycoprotein on the surface of highly pathogenic influenza A viruses. In Chapter 3, we hypothesized that synthetic miR-24 could inhibit highly pathogenic H5N1 influenza A infection. Addition of exogenous miR-24 during H5N1 infection resulted in a significant decrease in furin mRNA expression and enzymatic activity as well as reduced infectious virus released and virus spread. In Chapter 4, we hypothesized that novel miRNAs could target the proprotein convertase furin, along with two additional human proprotein convertases: PCSK9 and SKI-1/S1P, that have significant roles during the lifecycles of other enveloped viruses. We identified a novel miRNA, miR-17, that reduced furin mRNA and enzymatic activity. Furthermore, miR-24 was shown to target PCSK9, potentially contributing to the regulation of lipid metabolism. MiRNAs are now recognized as important players during virus infections, especially during the influenza A virus lifecycle. By exploiting the targets of specific miRNAs, we have identified new potential therapeutic options that could be applied to numerous enveloped viruses.
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Hepatitis C virus (HCV) utilizes host lipids for every stage of its lifecycle. HCV hijackshost lipid droplets (LDs) to coordinate assembly through the host lipoprotein assembly pathway;this facilitates uptake into hepatocytes through the low density lipoprotein receptor (LDLR).Induction of host lipid metabolism by HCV supports chronic infection and leads to steatosis,exacerbating liver dysfunction in infected patients. One pathway activated by HCV is the sterolregulatory element binding protein (SREBP) pathway which controls lipid metabolism geneexpression. To activate genes in the nucleus, SREBPs must first be cleaved by host subtilisinkexin isozyme-1/site-1 protease (SKI-1/S1P). Proprotein convertase subtilisin/kexin type 9(PCSK9) is one SREBP-regulated protein that post-translationally decreases LDLR expression inthe liver. The overall aim of this thesis was to determine the potential application of these twoimportant regulators of host lipid homeostasis, PCSK9 and SKI-1/S1P, as targets for inhibitingHCV infection.The first hypothesis tested was that inhibiting SKI-1/S1P would block HCV hijacking ofthe SREBP pathway and limit sequestration of host lipids by HCV, blocking virus propagation.To inhibit SKI-1/S1P function, an engineered serine protease inhibitor (serpin) and a smallmolecule inhibitor were employed. Both inhibitors were shown to block SKI-1/S1P cleavage ofSREBPs, reduce LD accumulation in hepatoma cells and inhibit HCV infection. The nexthypothesis explored was that amplifying PCSK9 expression or function in hepatoma cells wouldincrease their resistance to HCV infection through downregulation of LDLR. It was confirmed,using overexpression of wild-type PCSK9 or treating cells with gain-of-function PCSK9, thatPCSK9 can be used to prevent HCV entry into hepatoma cells. Finally, studies are presenteddetailing the discovery and characterization of a non-inhibitory serpin variant with potentantiviral activity against HCV infection. It is hypothesized that inhibition may be related toantiviral functions exhibited by other human serpins or serpin-derived peptides possessingdiverse regulatory properties.Host lipid metabolism is a critical component of the lifecycle of HCV and many otherviruses. These studies confirm that lipid metabolism pathways can be rationally targeted toinhibit viral infection and may lead to the development of novel, indirect-acting therapies againstHCV and related viruses.
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West Nile virus (WNV) is the most widely distributed arthropod-borne virus globally. It can cause a potentially fatal infection and has become a public health concern in North America since its introduction in 1999. Currently, there are no vaccines or treatments available for human WNV infections. As such, it is important to understand the virus life cycle, in order to develop effective therapeutics. The WNV protease heterocomplex, NS2B/NS3, is a prime target for antiviral therapy and has become the focus of much research. It is important to understand protease function first, in order to develop effective inhibitors. The overall goal of this thesis was to gain a better understanding into the function of the full-length NS2B/NS3 protease heterocomplex within the intracellular microenvironment. I hypothesized that there are critical residues essential for the interaction between NS2B and NS3 that affect protease activity and protein stability. The first aim of this project was to generate a cell-based fluorescent substrate assay to investigate the protease activity of the full-length NS2B/NS3 protease heterocomplex within the cell. My results demonstrate that the full-length NS2B/NS3 protease heterocomplex functions differently within the context of the cell, compared to what has been previously observed in vitro (Chapter 2). In the second aim, I investigated NS2B function on NS3 protease cis-cleavage and trans-cleavage activity. My results reveal an important dual role the NS2B protein plays in the proper function of the full-length NS2B/NS3 protease heterocomplex (Chapter 3). In the third aim, I utilized the information gathered to rationally design and test a serine protease inhibitor directed against the full-length NS2B/NS3 protease heterocomplex (Chapter 4). Taken together, my results highlight the importance of utilizing cell-based assays to assess protease activity, as this allows for the investigation of NS2B/NS3 protease function in a more physiologically relevant environment. The results presented in this thesis further our understanding of the activity of the full-length WNV NS2B/NS3 protease heterocomplex within the context of the cell. The information gathered gives insight into the regulation of viral protease function that could be utilized in the rational drug design towards the WNV NS2B/NS3 protease heterocomplex.
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No abstract available.
Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Since the onset of the pandemic, the proteolytic activation of SARS-CoV-2 spike glycoprotein has been a central topic of discussion. The evolution of the S1/S2 furin cleavage site reinvigorated the investigation of coronavirus spike cleavage at both S1/S2 and S2’ cleavage sites. In this study, we aimed to characterize the S2’ cleavage for both SARS-CoV-2 and hCoV-229E by developing a mass-spectrometry (MS) based quantification assay. To this end, we setup a series of biochemical assays using recombinant spike glycoproteins and various type II transmembrane proteases. These systems are then utilized to evaluate the currently available therapeutic candidates targeting the S2’ cleavage event. Remarkably, we observed the poor inhibition of S2’ activation by the widely used camostat and nafamostat in contrast to N-0385. Furthermore, we hypothesized that the evolution of the S1/S2 furin cleavage site enhances the activation of coronavirus at the S2’ site. To test this hypothesis, we established a set of transfection models to evaluate the activation state of the coronavirus spike. Both recombinant proteins and transfection systems are then utilized for the development of a MS-based assay. We explored techniques including N-terminal acetylation and various alternative proteases. In the end, LysC based methodology allowed for the distinguishing between cleaved and uncleaved S2’, revealing the role of TMPRSS2 in the activation of delta and BA.5 spike.Additionally, with the observation of neurological implications of SARS-CoV-2 infection, we explored the proteome of human astrocytes infected with hCoV-229E. The comparative proteomics analysis identified various dysregulated proteins and pathways providing the basis for future investigation in these potential pathogenic mechanisms.
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There is an urgent need for new antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19), because of reduced vaccine effectiveness to emerging variants of concern (VOCs) along with resistance to antibody therapeutics, and limitations present in current SARS-CoV-2 antivirals. A promising antiviral target is the SARS-CoV-2 main protease, also known as the 3-chymotrypsin-like protease (3CLpro), which plays an essential role in viral polyprotein processing. In a prior study (Ton et al., 2020), a 1.3 billion compound library was screened for potential 3CLpro inhibitors by using a Deep Docking (DD) platform to predict which molecules bind to the 3CLpro catalytic site. I hypothesize that compounds predicted by DD to bind to the SARS-CoV-2 3CLpro will present SARS-CoV-2 antiviral activity through inhibition of the 3CLpro. 604 potential 3CLpro inhibitors identified through DD were screened using an in vitro fluorescence resonance energy transfer (FRET)-based enzymatic assay with recombinant SARS-CoV-2 3CLpro. 15 of the molecules presented an inhibitory concentration 50 (IC₅₀) between 7-75 μM against 3CLpro. The best compound, C230, had an IC₅₀ of 74 ± 20 μM. In cellulo studies in Calu-3 lung cells showed that C230 had a mean effective concentration 50 (EC₅₀) of 17 μM against mNeonGreen (mNG) reporter SARS-CoV-2, was even more potent against SARS-CoV-2 Omicron BA.5, with EC₅₀ of 5 μM and 6 μM using nucleocapsid and dsRNA staining, respectively, and had a cytotoxic concentration 50 (CC₅₀) of > 100 μM. Additionally, an in cellulo enzymatic assay showed inhibition of recombinantly expressed SARS-CoV-2 3CLpro proteolytic activity in Caco-2 intestinal cells by 3CLpro inhibitors nirmatrelvir and GC376, with EC₅₀ values of 4.8 ± 0.4 μM and 8.0 ± 3.1 μM, respectively. Major findings of this study include the identification of novel 3CLpro inhibitors that display SARS-CoV-2 antiviral activity, validated through in vitro and in cellulo assays.
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Despite the discovery of the ability of coronaviruses to infect neural cells over 25 years ago, the underlying molecular processes and the impact of coronavirus infection on these cells remain poorly characterized. The emergence of SARS-CoV-2 has brought renewed attention to the importance of understanding coronavirus neurotropism. In this study, we aimed to investigate the infectability of primary human astrocytes with both SARS-CoV-2 variants and the common cold coronavirus HCoV-229E. Given the robust infection that HCoV-229E established in astrocytes at 33°C, we hypothesized that this coronavirus elicits dynamic temporal dysregulation of both miRNA and mRNA expression in astrocytes. To test this hypothesis, we performed the first comprehensive transcriptomic analysis to profile the temporal changes in miRNA and mRNA expression patterns in response to HCoV-229E infection in astrocytes. The primary objective of this study was to identify key molecular pathways that undergo dysregulation over time in coronavirus-infected astrocytes. Specifically, we aimed to compare the miRNAs that are commonly dysregulated by SARS-CoV-2 infection in bronchial epithelial cells with those observed in HCoV-229E-infected astrocytes. By doing so, we sought to determine whether the regulatory response to coronavirus infection in astrocytes shares similarities with that of bronchial epithelial cells. Understanding these shared regulatory mechanisms could shed light on the broader implications of coronavirus infections in different cell types. Remarkably, both models exhibited limited miRNA dysregulation despite robust levels of viral propagation. Significantly, miR-4443 and miR-1246 exhibited notable upregulation during the late stages of infection in both models of coronavirus infection. In-depth analysis of miRNA-mRNA interactions in these distinct models revealed multiple distinctive interactions, underscoring the context-dependent regulatory function of miRNAs within the infected cells. This study reveals novel miRNA and mRNA targets involved in coronavirus-host interactions within astrocytes, potentially providing new therapeutic targets for combating coronavirus infections. Additionally, the identified molecular alterations induced by HCoV-229E in astrocytes could also have broader implications for our understanding of the neuropathology and potential long-term consequences of coronavirus infections. Overall, this study represents a significant step towards unravelling the complex interplay between coronaviruses and the human CNS, with potential implications for both viral pathogenesis and therapeutic strategies.
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The Zika virus (ZIKV) is a positive-sense RNA flavivirus that has been determined as a causative agent of severe neurological diseases including Guillain-Barré syndrome and microcephaly. A common characteristic of flavivirus infection is the re-organization of host cell membranes, usually endoplasmic reticulum (ER) derived, to promote viral replication. As ZIKV-induced ER structures, being vesicular replication factories (RF) and convoluted membranes (CM), are smaller than the diffraction limit of light, studies to characterize these structures and their protein compositions have been limited. In this thesis, Stimulated Emission Depletion (STED) super resolution microscopy is utilized to study the whole cell organization of ZIKV-induced ER morphologies and several viral proteins involved in replication.Generally in cells, the ER can be divided into two regions, central ER sheets and peripheral ER tubules. Here we report the formation of an ZIKV-induced, organized crescent-shaped, dense central ER region of ER tubules. ZIKV RFs localize to this dense, central ER region in a similar crescent-shaped organization. Computational 3D reconstruction of these 3D STED imaged ZIKV-induced ER structures, along with validation by electron microscopy of ZIKV infected cerebral organoids, revealed that these dense ER regions are composed of novel smooth ER tubular matrices. Moreover, we have found that ZIKV NS4B, a viral encoded integral membrane protein predicted to play a role in ER membrane re-organization during ZIKV replication, is enriched in ZIKV-induced tubular matrices. Additionally, a subpopulation of ZIKV NS4B localizes to active RFs suggesting that NS4B plays a role in the formation of both ZIKV-induced tubular matrices and RFs among other functions. Overall, the application of super resolution microscopy to study ZIKV replication has led to the identification of novel ZIKV-induced, RF-containing tubular matrices and characterization of a viral protein involved in this process.
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Serpins (Serine Protease Inhibitors) are expressed by most organisms and perform a variety of functions. Most serpins inhibit proteases by undergoing a unique conformational change. They are clinically relevant in two ways. First, introduction of single amino acid point mutations transforms the serpins’ labile conformations into pathogenic, inactive polymers causing “serpinopathies”. In particular, human neuroserpin is a brain-specific serpin that, when mutated, causes a debilitating early onset dementia through unknown cellular pathways. Second, serpins are currently under investigation as therapeutic inhibitors of proprotein convertases (PCs). PCs are associated with some bacterial and viral infections as well as cancer. However, no comprehensive investigation into the cellular effects of PC inhibitor expression in mammalian cells has been performed. This thesis details the use of the Drosophila serpin, Spn4A, to address the cellular pathways mediated by serpin polymers or PC inhibition. Spn4A is a neuron-specific, secretory pathway serpin that inhibits Drosophila or human PCs. We hypothesized that Spn4A mutants, encoding homologous disease-causing mutations in human neuroserpin, would form pathogenic polymers and represent an ideal candidate for generating a cell-based and transgenic Drosophila serpinopathy model. Further, we hypothesized that we could evaluate the cellular response to PC inhibition and polymer accumulation by transcriptome profiling of H4 human neuroglioma cells expressing Spn4A wild-type and mutants. We established an expression system using Spn4A and its mutants in H4s. Subsequently, we used microarray analysis to simultaneously address how serpin polymers may induce cytotoxicity as well as the effects of proprotein processing inhibition in neuroglioma cells. We demonstrated that Spn4A mutants formed polymers, were retained in the endoplasmic reticulum, and lacked inhibitory function, but induced few changes on the transcriptome (under 20 genes differentially regulated). To this end, we have developed transgenic Drosophila overexpressing Spn4A variants to further investigate the biological impact of Spn4A mutants. Next, we analyzed the response to the PC inhibitor, Spn4A, and found marked changes in genes related to malignancy. Our genome-wide gene expression studies have provided novel insights into cellular changes in response to polymeric or PC-inhibiting serpins, and establish the foundation for future functional studies.
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Publications
- Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals (2024)
Antiviral Research, 225 - Optimization of Ketobenzothiazole-Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication (2024)
ChemMedChem, 19 (2) - A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants (2023)
Emerging Microbes and Infections, 12 (2) - Berbamine suppresses intestinal SARS-CoV-2 infection via a BNIP3-dependent autophagy blockade (2023)
Emerging Microbes and Infections, 12 (1) - Corrigendum to “Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics” “Antiviral Research 209 (2023)/105484” (Antiviral Research (2023) 209, (S0166354222002534), (10.1016/j.antiviral.2022.105484)) (2023)
Antiviral Research, 213 - Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics (2023)
Antiviral Research, 209 - Synthetic Analogs of the Sponge Sesterterpenoid Alotaketal C are Potent Inhibitors of SARS-CoV-2 Omicron BA.1 and BA.5 Infections of Human Lung Cells (2023)
Organic Letters, 25 (26), 4825-4829 - A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic (2022)
Nature, 605 (7909), 340-348 - DEEMD: Drug Efficacy Estimation Against SARS-CoV-2 Based on Cell Morphology With Deep Multiple Instance Learning (2022)
IEEE Transactions on Medical Imaging, 41 (11), 3128-3145 - Inhibition of glycogen synthase kinase-3-beta (GSK3β) blocks nucleocapsid phosphorylation and SARS-CoV-2 replication (2022)
Molecular Biomedicine, 3 (1) - Photodynamic and Contact Killing Polymeric Fabric Coating for Bacteria and SARS-CoV-2 (2022)
ACS Applied Materials and Interfaces, 14 (1), 49-56 - Automated discovery of noncovalent inhibitors of SARS-CoV-2 main protease by consensus Deep Docking of 40 billion small molecules (2021)
Chemical Science, 12 (48), 15960-15974 - Hijacking of lipid droplets by hepatitis C, dengue and zika viruses-from viral protein moonlighting to extracellular release (2020)
International Journal of Molecular Sciences, 21 (21), 1-18 - Super resolution microscopy and deep learning identify Zika virus reorganization of the endoplasmic reticulum (2020)
Scientific Reports, 10 (1) - Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents (2017)
PLoS ONE, 12 (3) - Moonlighting glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is required for efficient hepatitis c virus and dengue virus infections in human Huh-7.5.1 cells (2017)
Journal of General Virology, 98 (5), 977-991 - Treatment-Induced Viral Cure of Hepatitis C Virus-Infected Patients Involves a Dynamic Interplay among three Important Molecular Players in Lipid Homeostasis: Circulating microRNA (miR)-24, miR-223, and Proprotein Convertase Subtilisin/Kexin Type 9 (2017)
EBioMedicine, 23, 68-78 - Human microRNA-24 modulates highly pathogenic avian-origin H5N1 influenza A virus infection in A549 cells by targeting secretory pathway furin (2015)
Journal of General Virology, 96 (1), 30-39 - A Daphnane Diterpenoid isolated from Wikstroemia polyantha induces an inflammatory response and modulates miRNA activity (2012)
PLoS ONE, 7 (6) - Human subtilase SKI-1/S1P is a master regulator of the HCV lifecycle and a potential host cell target for developing indirect-acting antiviral agents (2012)
PLoS Pathogens, 8 (1) - Interleukin-7, but Not Thymic Stromal Lymphopoietin, Plays a Key Role in the T Cell Response to Influenza A Virus (2012)
PLoS ONE, 7 (11) - Pandemic H1N1 influenza infection and vaccination in humans induces cross-protective antibodies that target the hemagglutinin stem (2012)
Frontiers in Immunology, 3 (MAY) - Temporal- and strain-specific host microrna molecular signatures associated with swine-origin H1N1 and avian-origin H7N7 influenza a virus infection (2012)
Journal of Virology, 86 (11), 6109-6122 - In-cell selectivity profiling of membrane-anchored and replicase-associated hepatitis C virus NS3-4A protease reveals a common, stringent substrate recognition profile (2011)
Biological Chemistry, 392 (10), 927-935 - Modulation of PC1/3 activity by self-interaction and substrate binding (2011)
Endocrinology, 152 (4), 1402-1411 - Detection and in-cell selectivity profiling of the full-length West Nile virus NS2B/NS3 serine protease using membrane-anchored fluorescent substrates (2010)
Biological Chemistry, 391 (5), 549-559 - A SARS-coronovirus 3CL protease inhibitor isolated from the marine sponge Axinella cf. corrugata: Structure elucidation and synthesis (2007)
Journal of the Brazilian Chemical Society, 18 (2), 440-443 - Blockage of filoviral glycoprotein processing by use of a protein-based inhibitor (2007)
Journal of Infectious Diseases, 196 (SUPPL. 2) - Development of a red-shifted fluorescence-based assay for SARS-coronavirus 3CL protease: Identification of a novel class of anti-SARS agents from the tropical marine sponge Axinella corrugata (2006)
Biological Chemistry, 387 (8), 1063-1074 - Identification of a pH sensor in the furin propeptide that regulates enzyme activation (2006)
Journal of Biological Chemistry, 281 (23), 16108-16116 - Single-cell resolution imaging of membrane-anchored hepatitis C virus NS3/4A protease activity (2006)
Biological Chemistry, 387 (8), 1075-1080 - Enzymatic characterization of membrane-associated hepatitis C virus NS3-4A heterocomplex serine protease activity expressed in human cells (2005)
Biochemistry, 44 (17), 6586-6596 - Cleavages within the prodomain direct intracellular trafficking and degradation of mature bone morphogenetic protein-4 (2004)
Molecular Biology of the Cell, 15 (11), 5012-5020 - Hepatitis C virus NS3 RNA helicase activity is modulated by the two domains of NS3 and NS4A (2004)
Biochemical and Biophysical Research Communications, 317 (1), 211-217 - Serpin mechanism of hepatitis C virus nonstructural 3 (NS3) protease inhibition: Induced fit as a mechanism for narrow specificity (2004)
Journal of Biological Chemistry, 279 (11), 10222-10227 - The Spn4 gene of Drosophila encodes a potent furin-directed secretory pathway serpin (2004)
Proceedings of the National Academy of Sciences of the United States of America, 101 (29), 10560-10565 - The ordered and compartment-specific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation (2002)
Journal of Biological Chemistry, 277 (15), 12879-12890 - The activity and signaling range of mature BMP-4 is regulated by sequential cleavage at two sites within the prodomain of the precursor (2001)
Genes and Development, 15 (21), 2797-2802 - A protein-based therapeutic for human cytomegalovirus infection (2000)
Proceedings of the National Academy of Sciences of the United States of America, 97 (6), 2864-2869 - Bi-cycling the furin pathway: From TGN localization to pathogen activation and embryogenesis (1999)
Trends in Cell Biology, 9 (1), 28-35 - BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development (1998)
EMBO Journal, 17 (16), 4735-4743 - In vitro cleavage of internally quenched fluorogenic human proparathyroid hormone and proparathyroid-related peptide substrates by furin. Generation of a potent inhibitor (1998)
Journal of Biological Chemistry, 273 (15), 8572-8580 - Inhibition of soluble recombinant furin by human proteinase inhibitor 8 (1998)
Journal of Biological Chemistry, 273 (4), 1851-1854 - The pore-forming toxin proaerolysin is activated by furin (1998)
Journal of Biological Chemistry, 273 (49), 32656-32661 - α1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: Application as an antipathogenic agent (1998)
Proceedings of the National Academy of Sciences of the United States of America, 95 (13), 7293-7298 - Activation of the furin endoprotease is a multiple-step process: Requirements for acidification and internal propeptide cleavage (1997)
EMBO Journal, 16 (7), 1508-1518 - An internally quenched fluorogenic substrate of prohormone convertase 1 and furin leads to a potent prohormone convertase inhibitor (1995)
Biochemical Journal, 307 (3), 689-695 - Fluorescent peptidyl substrates as an aid in studying the substrate specificity of human prohormone convertase PC1 and human furin and designing a potent irreversible inhibitor (1995)
Journal of Biological Chemistry, 270 (33), 19225-19231 - Biotinylation of an Enkephalin-Containing Heptapeptide via Various Spacer Arms. Synthesis, Comparative Binding Studies toward Avidin, and Application as Substrates in Enzymatic Reactions (1994)
Bioconjugate Chemistry, 5 (4), 301-305 - Design and synthesis of novel inhibitors of prohormone convertases (1994)
International Journal of Peptide and Protein Research, 44 (3), 253-261 - The convertases furin and PC1 can both cleave the human immunodeficiency virus (HIV)-1 envelope glycoprotein gp160 into gp120 (HIV-I SU) and gp41 (HIV-I TM) (1994)
Journal of Biological Chemistry, 269 (16), 12240-12247 - Enzymic characterization of murine and human prohormone convertase-1 (mPC1 and hPC1) expressed in mammalian GH4C1 cells (1993)
Biochemical Journal, 292 (3), 891-900 - Radiolabeled biotinyl peptides as useful reagents for the study of proteolytic enzymes (1993)
Analytical Biochemistry, 209 (2), 306-314 - Detection of endopeptidase activity and analysis of cleavage specificity using a radiometric solid-phase enzymatic assay (1991)
Analytical Biochemistry, 194 (2), 399-406 - Syntheses of argininal semicarbazone containing peptides and their applications in the affinity chromatography of serine proteinases (1990)
International Journal of Peptide and Protein Research, 36 (1), 7-17
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