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1.
J Med Chem ; 64(19): 14332-14343, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1621195

ABSTRACT

In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.


Subject(s)
Calixarenes/chemistry , Cell Adhesion Molecules/antagonists & inhibitors , Glycoconjugates/metabolism , Glycoproteins/antagonists & inhibitors , Hydroxamic Acids/chemistry , Lectins, C-Type/antagonists & inhibitors , Phenols/chemistry , Receptors, Cell Surface/antagonists & inhibitors , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Cell Adhesion Molecules/metabolism , Cell Line , Cytomegalovirus/metabolism , Dendritic Cells/cytology , Dendritic Cells/metabolism , Ebolavirus/physiology , Glycoconjugates/chemistry , Glycoconjugates/pharmacology , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Jurkat Cells , Lectins, C-Type/metabolism , Models, Biological , Protein Binding , Receptors, Cell Surface/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Viral Proteins/genetics , Viral Proteins/metabolism
2.
Int J Mol Sci ; 22(3)2021 Jan 22.
Article in English | MEDLINE | ID: covidwho-1389387

ABSTRACT

In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein-protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.


Subject(s)
Genes, MHC Class II , NLR Proteins/metabolism , Nuclear Proteins/metabolism , Trans-Activators/metabolism , Animals , COVID-19/genetics , COVID-19/metabolism , Ebolavirus/physiology , Gene Expression Regulation , Hemorrhagic Fever, Ebola/genetics , Hemorrhagic Fever, Ebola/metabolism , Humans , NLR Proteins/genetics , Neoplasms/genetics , Neoplasms/metabolism , Nuclear Proteins/genetics , Protein Interaction Maps , SARS-CoV-2/physiology , Trans-Activators/genetics , Virus Replication
3.
STAR Protoc ; 2(4): 100818, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1373302

ABSTRACT

Experimental work on highly pathogenic viruses such as Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus-2 requires high-level biosafety facilities. Here, we provide a detailed step-by-step protocol which details the production and application of replication-incompetent murine leukemia virus-based pseudotyped particles to monitor and quantify the viral entry efficiency in human cell lines under biosafety level-2 conditions. We describe the use of viral particles encoding luciferase gene and the quantification of transduction efficiency by measuring luciferase activity. For complete details on the use and execution of this protocol, please refer to Imre et al. (2021).


Subject(s)
COVID-19/diagnosis , Ebolavirus/physiology , Hemorrhagic Fever, Ebola/diagnosis , SARS-CoV-2/physiology , Virus Internalization , COVID-19/virology , HEK293 Cells , Hemorrhagic Fever, Ebola/virology , Humans , Virion
5.
FEBS Open Bio ; 11(5): 1452-1464, 2021 05.
Article in English | MEDLINE | ID: covidwho-1168813

ABSTRACT

Human pathogenic RNA viruses are threats to public health because they are prone to escaping the human immune system through mutations of genomic RNA, thereby causing local outbreaks and global pandemics of emerging or re-emerging viral diseases. While specific therapeutics and vaccines are being developed, a broad-spectrum therapeutic agent for RNA viruses would be beneficial for targeting newly emerging and mutated RNA viruses. In this study, we conducted a screen of repurposed drugs using Sendai virus (an RNA virus of the family Paramyxoviridae), with human-induced pluripotent stem cells (iPSCs) to explore existing drugs that may present anti-RNA viral activity. Selected hit compounds were evaluated for their efficacy against two important human pathogens: Ebola virus (EBOV) using Huh7 cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using Vero E6 cells. Selective estrogen receptor modulators (SERMs), including raloxifene, exhibited antiviral activities against EBOV and SARS-CoV-2. Pioglitazone, a PPARγ agonist, also exhibited antiviral activities against SARS-CoV-2, and both raloxifene and pioglitazone presented a synergistic antiviral effect. Finally, we demonstrated that SERMs blocked entry steps of SARS-CoV-2 into host cells. These findings suggest that the identified FDA-approved drugs can modulate host cell susceptibility against RNA viruses.


Subject(s)
Antiviral Agents/pharmacology , Drug Repositioning , RNA Viruses/drug effects , RNA, Viral/antagonists & inhibitors , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , Cell Line , Chlorocebus aethiops , Drug Repositioning/methods , Ebolavirus/drug effects , Ebolavirus/physiology , Humans , Induced Pluripotent Stem Cells/virology , Microbial Sensitivity Tests/methods , Pioglitazone/pharmacology , RNA Viruses/physiology , Raloxifene Hydrochloride/pharmacology , SARS-CoV-2/physiology , Selective Estrogen Receptor Modulators/pharmacology , Sendai virus/drug effects , Sendai virus/physiology , Vero Cells
6.
Antiviral Res ; 186: 104990, 2021 02.
Article in English | MEDLINE | ID: covidwho-1064808

ABSTRACT

The endocytic pathway is a common strategy that several highly pathogenic viruses use to enter into the cell. To demonstrate the usefulness of this pathway as a common target for the development of broad-spectrum antivirals, the inhibitory effect of drug compounds targeting endosomal membrane proteins were investigated. This study entailed direct comparison of drug effectiveness against animal and human pathogenic viruses, namely Ebola (EBOV), African swine fever virus (ASFV), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A panel of experimental and FDA-approved compounds targeting calcium channels and PIKfyve at the endosomal membrane caused potent reductions of entry up to 90% in SARS-CoV-2 S-protein pseudotyped retrovirus. Similar inhibition was observed against transduced EBOV glycoprotein pseudovirus and ASFV. SARS-CoV-2 infection was potently inhibited by selective estrogen receptor modulators in cells transduced with pseudovirus, among them Raloxifen inhibited ASFV with very low 50% inhibitory concentration. Finally, the mechanism of the inhibition caused by the latter in ASFV infection was analyzed. Overall, this work shows that cellular proteins related to the endocytic pathway can constitute suitable cellular targets for broad range antiviral compounds.


Subject(s)
African Swine Fever Virus/drug effects , Antiviral Agents/pharmacology , Ebolavirus/drug effects , Endosomes/drug effects , SARS-CoV-2/drug effects , Virus Internalization/drug effects , African Swine Fever Virus/physiology , Animals , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Cell Line , Cell Line, Tumor , Chlorocebus aethiops , Cholesterol/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Ebolavirus/physiology , Endocytosis/drug effects , Endosomes/metabolism , Humans , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Raloxifene Hydrochloride/pharmacology , Receptors, Estrogen/metabolism , SARS-CoV-2/physiology , Selective Estrogen Receptor Modulators/pharmacology , Vero Cells
7.
Int J Mol Sci ; 22(3)2021 Jan 22.
Article in English | MEDLINE | ID: covidwho-1045412

ABSTRACT

In this review, we discuss the major histocompatibility complex (MHC) class II transactivator (CIITA), which is the master regulator of MHC class II gene expression. CIITA is the founding member of the mammalian nucleotide-binding and leucine-rich-repeat (NLR) protein family but stood apart for a long time as the only transcriptional regulator. More recently, it was found that its closest homolog, NLRC5 (NLR protein caspase activation and recruitment domain (CARD)-containing 5), is a regulator of MHC-I gene expression. Both act as non-DNA-binding activators through multiple protein-protein interactions with an MHC enhanceosome complex that binds cooperatively to a highly conserved combinatorial cis-acting module. Thus, the regulation of MHC-II expression is regulated largely through the differential expression of CIITA. In addition to the well-defined role of CIITA in MHC-II GENE regulation, we will discuss several other aspects of CIITA functions, such as its role in cancer, its role as a viral restriction element contributing to intrinsic immunity, and lastly, its very recently discovered role as an inhibitor of Ebola and SARS-Cov-2 virus replication. We will briefly touch upon the recently discovered role of NLRP3 as a transcriptional regulator, which suggests that transcriptional regulation is, after all, not such an unusual feature for NLR proteins.


Subject(s)
Genes, MHC Class II , NLR Proteins/metabolism , Nuclear Proteins/metabolism , Trans-Activators/metabolism , Animals , COVID-19/genetics , COVID-19/metabolism , Ebolavirus/physiology , Gene Expression Regulation , Hemorrhagic Fever, Ebola/genetics , Hemorrhagic Fever, Ebola/metabolism , Humans , NLR Proteins/genetics , Neoplasms/genetics , Neoplasms/metabolism , Nuclear Proteins/genetics , Protein Interaction Maps , SARS-CoV-2/physiology , Trans-Activators/genetics , Virus Replication
8.
PLoS One ; 15(12): e0243270, 2020.
Article in English | MEDLINE | ID: covidwho-965212

ABSTRACT

The SARS-CoV-2 (COVID-19) pandemic is a global crisis that threatens our way of life. As of November 18, 2020, SARS-CoV-2 has claimed more than 1,342,709 lives, with a global mortality rate of ~2.4% and a recovery rate of ~69.6%. Understanding the interaction of cellular targets with the SARS-CoV-2 infection is crucial for therapeutic development. Therefore, the aim of this study was to perform a comparative analysis of transcriptomic signatures of infection of SARS-CoV-2 compared to other respiratory viruses (EBOV, H1N1, MERS-CoV, and SARS-CoV), to determine a unique anti-SARS-CoV-2 gene signature. We identified for the first time that molecular pathways for heparin-binding, RAGE, miRNA, and PLA2 inhibitors were associated with SARS-CoV-2 infection. The NRCAM and SAA2 genes, which are involved in severe inflammatory responses, and the FGF1 and FOXO1 genes, which are associated with immune regulation, were found to be associated with the cellular gene response to SARS-CoV-2 infection. Moreover, several cytokines, most significantly IL-8 and IL-6, demonstrated key associations with SARS-CoV-2 infection. Interestingly, the only response gene that was shared among the five viral infections was SERPINB1. The protein-protein interaction (PPI) analysis shed light on genes with high interaction activity that SARS-CoV-2 shares with other viral infections. The findings showed that the genetic pathways associated with rheumatoid arthritis, the AGE-RAGE signaling system, malaria, hepatitis B, and influenza A were of high significance. We found that the virogenomic transcriptome of infection, gene modulation of host antiviral responses, and GO terms of SARS-CoV-2 and EBOV were more similar than to SARS, H1N1, and MERS. This work compares the virogenomic signatures of highly pathogenic viruses and provides valid targets for potential therapy against SARS-CoV-2.


Subject(s)
COVID-19/genetics , SARS-CoV-2/physiology , Transcriptome , COVID-19/metabolism , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Ebolavirus/physiology , Gene Expression Profiling , Hemorrhagic Fever, Ebola/genetics , Hemorrhagic Fever, Ebola/metabolism , Host-Pathogen Interactions , Humans , Influenza A Virus, H1N1 Subtype/physiology , Influenza, Human/genetics , Influenza, Human/metabolism , Middle East Respiratory Syndrome Coronavirus/physiology , Protein Interaction Maps , SARS Virus/physiology
9.
Viruses ; 12(12)2020 12 10.
Article in English | MEDLINE | ID: covidwho-969583

ABSTRACT

Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies.


Subject(s)
Antiviral Agents/pharmacology , Host-Pathogen Interactions/drug effects , RNA Viruses/drug effects , Virus Replication/drug effects , Animals , Cell Line , Ebolavirus/drug effects , Ebolavirus/physiology , HSP70 Heat-Shock Proteins/metabolism , Hemorrhagic Fever Virus, Crimean-Congo/drug effects , Hemorrhagic Fever Virus, Crimean-Congo/physiology , Humans , Protein Binding/drug effects , Protein Stability , Proteome/drug effects , Proteostasis/drug effects , RNA Virus Infections/metabolism , RNA Virus Infections/virology , RNA Viruses/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Small Molecule Libraries/pharmacology , Viral Proteins/metabolism
11.
Antiviral Res ; 182: 104874, 2020 10.
Article in English | MEDLINE | ID: covidwho-891945

ABSTRACT

Based on genome-scale loss-of-function screens we discovered that Topoisomerase III-ß (TOP3B), a human topoisomerase that acts on DNA and RNA, is required for yellow fever virus and dengue virus-2 replication. Remarkably, we found that TOP3B is required for efficient replication of all positive-sense-single stranded RNA viruses tested, including SARS-CoV-2. While there are no drugs that specifically inhibit this topoisomerase, we posit that TOP3B is an attractive anti-viral target.


Subject(s)
Betacoronavirus/physiology , DNA Topoisomerases, Type I/metabolism , RNA Viruses/metabolism , Virus Replication/physiology , Cell Line , Dengue Virus/physiology , Ebolavirus/physiology , Gene Knockout Techniques , Humans , Influenza A virus/physiology , SARS-CoV-2 , Yellow fever virus/physiology , Zika Virus/physiology
12.
mBio ; 11(5)2020 09 15.
Article in English | MEDLINE | ID: covidwho-772275

ABSTRACT

Membrane-associated RING-CH-type 8 (MARCH8) strongly blocks human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) incorporation into virions by downregulating its cell surface expression, but the mechanism is still unclear. We now report that MARCH8 also blocks the Ebola virus (EBOV) glycoprotein (GP) incorporation via surface downregulation. To understand how these viral fusion proteins are downregulated, we investigated the effects of MARCH8 on EBOV GP maturation and externalization via the conventional secretion pathway. MARCH8 interacted with EBOV GP and furin when detected by immunoprecipitation and retained the GP/furin complex in the Golgi when their location was tracked by a bimolecular fluorescence complementation (BiFC) assay. MARCH8 did not reduce the GP expression or affect the GP modification by high-mannose N-glycans in the endoplasmic reticulum (ER), but it inhibited the formation of complex N-glycans on the GP in the Golgi. Additionally, the GP O-glycosylation and furin-mediated proteolytic cleavage were also inhibited. Moreover, we identified a novel furin cleavage site on EBOV GP and found that only those fully glycosylated GPs were processed by furin and incorporated into virions. Furthermore, the GP shedding and secretion were all blocked by MARCH8. MARCH8 also blocked the furin-mediated cleavage of HIV-1 Env (gp160) and the highly pathogenic avian influenza virus H5N1 hemagglutinin (HA). We conclude that MARCH8 has a very broad antiviral activity by prohibiting different viral fusion proteins from glycosylation and proteolytic cleavage in the Golgi, which inhibits their transport from the Golgi to the plasma membrane and incorporation into virions.IMPORTANCE Enveloped viruses express three classes of fusion proteins that are required for their entry into host cells via mediating virus and cell membrane fusion. Class I fusion proteins are produced from influenza viruses, retroviruses, Ebola viruses, and coronaviruses. They are first synthesized as a type I transmembrane polypeptide precursor that is subsequently glycosylated and oligomerized. Most of these precursors are cleaved en route to the plasma membrane by a cellular protease furin in the late secretory pathway, generating the trimeric N-terminal receptor-binding and C-terminal fusion subunits. Here, we show that a cellular protein, MARCH8, specifically inhibits the furin-mediated cleavage of EBOV GP, HIV-1 Env, and H5N1 HA. Further analyses uncovered that MARCH8 blocked the EBOV GP glycosylation in the Golgi and inhibited its transport from the Golgi to the plasma membrane. Thus, MARCH8 has a very broad antiviral activity by specifically inactivating different viral fusion proteins.


Subject(s)
Ebolavirus/chemistry , Glycoproteins/antagonists & inhibitors , HIV-1/chemistry , Hemagglutinins, Viral/metabolism , Influenza A Virus, H5N1 Subtype/chemistry , Ubiquitin-Protein Ligases/genetics , Viral Envelope Proteins/antagonists & inhibitors , Viral Envelope Proteins/physiology , Animals , Cell Line , Chlorocebus aethiops , Ebolavirus/physiology , Glycosylation , HEK293 Cells , HIV-1/physiology , HeLa Cells , Hep G2 Cells , Humans , Influenza A Virus, H5N1 Subtype/physiology , Protein Binding , THP-1 Cells , Ubiquitin-Protein Ligases/metabolism , Vero Cells , Viral Fusion Proteins/antagonists & inhibitors , Viral Fusion Proteins/metabolism
13.
Appl Environ Microbiol ; 86(17)2020 08 18.
Article in English | MEDLINE | ID: covidwho-767717

ABSTRACT

The infection of health care workers during the 2013 to 2016 Ebola outbreak raised concerns about fomite transmission. In the wake of the coronavirus disease 2019 (COVID-19) pandemic, investigations are ongoing to determine the role of fomites in coronavirus transmission as well. The bacteriophage phi 6 has a phospholipid envelope and is commonly used in environmental studies as a surrogate for human enveloped viruses. The persistence of phi 6 was evaluated as a surrogate for Ebola virus (EBOV) and coronaviruses on porous and nonporous hospital surfaces. Phi 6 was suspended in a body fluid simulant and inoculated onto 1-cm2 coupons of steel, plastic, and two fabric curtain types. The coupons were placed at two controlled absolute humidity (AH) levels: a low AH of 3.0 g/m3 and a high AH of 14.4 g/m3 Phi 6 declined at a lower rate on all materials under low-AH conditions, with a decay rate of 0.06-log10 PFU/day to 0.11-log10 PFU/day, than under the higher AH conditions, with a decay rate of 0.65-log10 PFU/h to 1.42-log10 PFU/day. There was a significant difference in decay rates between porous and nonporous surfaces at both low AH (P < 0.0001) and high AH (P < 0.0001). Under these laboratory-simulated conditions, phi 6 was found to be a conservative surrogate for EBOV under low-AH conditions in that it persisted longer than Ebola virus in similar AH conditions. Additionally, some coronaviruses persist longer than phi 6 under similar conditions; therefore, phi 6 may not be a suitable surrogate for coronaviruses.IMPORTANCE Understanding the persistence of enveloped viruses helps inform infection control practices and procedures in health care facilities and community settings. These data convey to public health investigators that enveloped viruses can persist and remain infective on surfaces, thus demonstrating a potential risk for transmission. Under these laboratory-simulated Western indoor hospital conditions, we assessed the suitability of phi 6 as a surrogate for environmental persistence research related to enveloped viruses, including EBOV and coronaviruses.


Subject(s)
Bacteriophage phi 6/isolation & purification , Bacteriophage phi 6/physiology , Coronavirus/physiology , Ebolavirus/physiology , Environmental Microbiology , Fomites/virology , Virus Inactivation , Betacoronavirus/physiology , COVID-19 , Coronavirus/isolation & purification , Coronavirus Infections/transmission , Coronavirus Infections/virology , Ebolavirus/isolation & purification , Hemorrhagic Fever, Ebola/transmission , Hemorrhagic Fever, Ebola/virology , Hospitals , Humans , Humidity , Pandemics , Pneumonia, Viral/transmission , Porosity , SARS-CoV-2 , Temperature
14.
Science ; 370(6513): 241-247, 2020 10 09.
Article in English | MEDLINE | ID: covidwho-733186

ABSTRACT

Recent outbreaks of Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed our limited therapeutic options for such diseases and our poor understanding of the cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. We further show that CD74 p41 can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. These data therefore implicate CIITA and CD74 in host defense against a range of viruses, and they identify an additional function of these proteins beyond their canonical roles in antigen presentation.


Subject(s)
Antigens, Differentiation, B-Lymphocyte/physiology , Betacoronavirus/physiology , Coronavirus Infections/immunology , Ebolavirus/physiology , Hemorrhagic Fever, Ebola/immunology , Histocompatibility Antigens Class II/physiology , Host-Pathogen Interactions/immunology , Nuclear Proteins/physiology , Pneumonia, Viral/immunology , Trans-Activators/physiology , Virus Internalization , Antigens, Differentiation, B-Lymphocyte/genetics , COVID-19 , Cell Line, Tumor , Coronavirus Infections/virology , DNA Transposable Elements , Endosomes/virology , Genetic Testing , Hemorrhagic Fever, Ebola/virology , Histocompatibility Antigens Class II/genetics , Host-Pathogen Interactions/genetics , Humans , Nuclear Proteins/genetics , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Trans-Activators/genetics , Transcription, Genetic
15.
Proc Natl Acad Sci U S A ; 117(34): 20803-20813, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-695945

ABSTRACT

Virus entry is a multistep process. It initiates when the virus attaches to the host cell and ends when the viral contents reach the cytosol. Genetically unrelated viruses can subvert analogous subcellular mechanisms and use similar trafficking pathways for successful entry. Antiviral strategies targeting early steps of infection are therefore appealing, particularly when the probability for successful interference through a common step is highest. We describe here potent inhibitory effects on content release and infection by chimeric vesicular stomatitis virus (VSV) containing the envelope proteins of Zaire ebolavirus (VSV-ZEBOV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (VSV-SARS-CoV-2) elicited by Apilimod and Vacuolin-1, small-molecule inhibitors of the main endosomal phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, PIKfyve. We also describe potent inhibition of SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 by Apilimod. These results define tools for studying the intracellular trafficking of pathogens elicited by inhibition of PIKfyve kinase and suggest the potential for targeting this kinase in developing small-molecule antivirals against SARS-CoV-2.


Subject(s)
Betacoronavirus/drug effects , Ebolavirus/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Morpholines/pharmacology , Phosphatidylinositol 3-Kinases , Triazines/pharmacology , Virus Internalization/drug effects , Animals , Betacoronavirus/physiology , COVID-19 , Cells, Cultured , Coronavirus Infections , Ebolavirus/physiology , Gene Editing , Humans , Hydrazones , Pandemics , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Pneumonia, Viral , Pyrimidines , SARS-CoV-2 , Viral Envelope Proteins/genetics
16.
Rev Med Virol ; 30(6): 1-13, 2020 11.
Article in English | MEDLINE | ID: covidwho-688978

ABSTRACT

Since the emergence of coronavirus disease 2019 (Covid-19), many studies have been performed to characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and find the optimum way to combat this virus. After suggestions and assessments of several therapeutic options, remdesivir (GS-5734), a direct-acting antiviral drug previously tested against Ebola virus disease, was found to be moderately effective and probably safe for inhibiting SARS-CoV-2 replication. Finally, on 1 May 2020, remdesivir (GS-5734) was granted emergency use authorization as an investigational drug for the treatment of Covid-19 by the Food and Drug Administration. However, without a doubt, there are challenging days ahead. Here, we provide a review of the latest findings (based on preprints, post-prints, and news releases in scientific websites) related to remdesivir efficacy and safety for the treatment of Covid-19, along with covering remdesivir history from bench-to-bedside, as well as an overview of its mechanism of action. In addition, active clinical trials, as well as challenging issues related to the future of remdesivir in Covid-19, are covered. Up to the date of writing this review (19 May 2020), there is one finished randomized clinical trial and two completed non-randomized studies, in addition to some ongoing studies, including three observational studies, two expanded access studies, and seven active clinical trials registered on the clinicaltrials.gov and isrctn.com websites. Based on these studies, it seems that remdesivir could be an effective and probably safe treatment option for Covid-19. However, more randomized controlled studies are required.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Hemorrhagic Fever, Ebola/drug therapy , Hemorrhagic Fever, Ebola/virology , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Clinical Trials as Topic , Ebolavirus/drug effects , Ebolavirus/physiology , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Treatment Outcome , Virus Replication/drug effects
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