Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 19 de 19
Filter
3.
Cell ; 184(24): 5950-5969.e22, 2021 11 24.
Article in English | MEDLINE | ID: covidwho-1499701

ABSTRACT

The biogenesis of mammalian autophagosomes remains to be fully defined. Here, we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. A previously unrecognized apparatus defined here controls HyPAS biogenesis and mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes, which emerge via convergence of secretory and endosomal pathways, and show that this process is targeted by microbial factors such as coronaviral membrane-modulating proteins.


Subject(s)
Autophagosomes/virology , COVID-19/virology , Autophagy , COVID-19/metabolism , CRISPR-Cas Systems , Cell Line, Tumor , Endoplasmic Reticulum/metabolism , Endosomes/physiology , Endosomes/virology , Golgi Apparatus/physiology , HEK293 Cells , HeLa Cells , Humans , Membrane Fusion , Microscopy, Confocal , Phagosomes/metabolism , Phagosomes/virology , Qa-SNARE Proteins/biosynthesis , Receptors, sigma/biosynthesis , SARS-CoV-2 , Sarcoplasmic Reticulum Calcium-Transporting ATPases/biosynthesis , Synaptotagmins/biosynthesis
4.
J Cell Biochem ; 123(2): 155-160, 2022 02.
Article in English | MEDLINE | ID: covidwho-1473858

ABSTRACT

Drug repurposing is an attractive option for identifying new treatment strategies, in particular in extraordinary situations of urgent need such as the current coronavirus disease 2019 (Covid-19) pandemic. Recently, the World Health Organization announced testing of three drugs as potential Covid-19 therapeutics that are known for their dampening effect on the immune system. Thus, the underlying concept of selecting these drugs is to temper the potentially life-threatening overshooting of the immune system reacting to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. This viewpoint discusses the possibility that the impact of these and other drugs on autophagy contributes to their therapeutic effect by hampering the SARS-CoV-2 life cycle.


Subject(s)
Antiviral Agents/pharmacology , Artesunate/pharmacology , Autophagy/drug effects , COVID-19/drug therapy , Drug Repositioning , Imatinib Mesylate/pharmacology , Infliximab/pharmacology , Pandemics , SARS-CoV-2/drug effects , Antidepressive Agents/pharmacology , Antiviral Agents/therapeutic use , Artesunate/therapeutic use , Chloroquine/pharmacology , Drug Development , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/physiology , Endoplasmic Reticulum/virology , Endosomes/drug effects , Endosomes/virology , Humans , Hydroxychloroquine/pharmacology , Imatinib Mesylate/therapeutic use , Infliximab/therapeutic use , Intracellular Membranes/drug effects , Intracellular Membranes/physiology , Intracellular Membranes/virology , Ivermectin/pharmacology , Macrolides/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Niclosamide/pharmacology , Niclosamide/therapeutic use , RNA, Viral/metabolism , SARS-CoV-2/physiology , Virus Replication
5.
J Cell Biochem ; 123(2): 161-182, 2022 02.
Article in English | MEDLINE | ID: covidwho-1405827

ABSTRACT

Viruses are known to cause various diseases in human and also infect other species such as animal plants, fungi, and bacteria. Replication of viruses depends upon their interaction with hosts. Human cells are prone to such unwanted viral infections. Disintegration and reconstitution require host machinery and various macromolecules like DNA, RNA, and proteins are invaded by viral particles. E3 ubiquitin ligases are known for their specific function, that is, recognition of their respective substrates for intracellular degradation. Still, we do not understand how ubiquitin proteasome system-based enzymes E3 ubiquitin ligases do their functional interaction with different viruses. Whether E3 ubiquitin ligases help in the elimination of viral components or viruses utilize their molecular capabilities in their intracellular propagation is not clear. The first time our current article comprehends fundamental concepts and new insights on the different viruses and their interaction with various E3 Ubiquitin Ligases. In this review, we highlight the molecular pathomechanism of viruses linked with E3 Ubiquitin Ligases dependent mechanisms. An enhanced understanding of E3 Ubiquitin Ligase-mediated removal of viral proteins may open new therapeutic strategies against viral infections.


Subject(s)
Ubiquitin-Protein Ligases/physiology , Viral Proteins/physiology , Virus Diseases/enzymology , Virus Replication/physiology , COVID-19/drug therapy , Cell Transformation, Viral/physiology , Cullin Proteins/physiology , Endosomes/virology , Host-Pathogen Interactions , Humans , Immunity, Innate , Inflammation/enzymology , Inflammation/virology , Neoplasms/enzymology , Neoplasms/virology , Oncogenic Viruses/physiology , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Tripartite Motif Proteins/physiology , Ubiquitin-Protein Ligases/antagonists & inhibitors , Virus Diseases/immunology , Virus Diseases/virology , Virus Replication/drug effects
6.
FEBS J ; 288(17): 5071-5088, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1393880

ABSTRACT

While there is undeniable evidence to link endosomal acid-base homeostasis to viral pathogenesis, the lack of druggable molecular targets has hindered translation from bench to bedside. The recent identification of variants in the interferon-inducible endosomal Na+ /H+ exchanger 9 associated with severe coronavirus disease-19 (COVID-19) has brought a shift in the way we envision aberrant endosomal acidification. Is it linked to an increased susceptibility to viral infection or a propensity to develop critical illness? This review summarizes the genetic and cellular evidence linking endosomal Na+ /H+ exchangers and viral diseases to suggest how they can act as a broad-spectrum modulator of viral infection and downstream pathophysiology. The review also presents novel insights supporting the complex role of endosomal acid-base homeostasis in viral pathogenesis and discusses the potential causes for negative outcomes of clinical trials utilizing alkalinizing drugs as therapies for COVID-19. These findings lead to a pathogenic model of viral disease that predicts that nonspecific targeting of endosomal pH might fail, even if administered early on, and suggests that endosomal Na+ /H+ exchangers may regulate key host antiviral defence mechanisms and mediators that act to drive inflammatory organ injury.


Subject(s)
COVID-19/therapy , SARS-CoV-2/pathogenicity , Sodium-Hydrogen Exchangers/genetics , Virus Diseases/therapy , COVID-19/genetics , COVID-19/virology , Endosomes/genetics , Endosomes/virology , Humans , Protons , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Virus Diseases/genetics , Virus Diseases/virology
7.
Antiviral Res ; 194: 105167, 2021 10.
Article in English | MEDLINE | ID: covidwho-1370440

ABSTRACT

Niemann-Pick type C1 (NPC1) receptor is an endosomal membrane protein that regulates intracellular cholesterol traffic. This protein has been shown to play an important role for several viruses. It has been reported that SARS-CoV-2 enters the cell through plasma membrane fusion and/or endosomal entry upon availability of proteases. However, the whole process is not fully understood yet and additional viral/host factors might be required for viral fusion and subsequent viral replication. Here, we report a novel interaction between the SARS-CoV-2 nucleoprotein (N) and the cholesterol transporter NPC1. Furthermore, we have found that some compounds reported to interact with NPC1, carbazole SC816 and sulfides SC198 and SC073, were able to reduce SARS-CoV-2 viral infection with a good selectivity index in human cell infection models. These findings suggest the importance of NPC1 for SARS-CoV-2 viral infection and a new possible potential therapeutic target to fight against COVID-19.


Subject(s)
Biological Transport , COVID-19/drug therapy , Endosomes/virology , Niemann-Pick C1 Protein/analysis , SARS-CoV-2/physiology , Animals , Carbazoles/pharmacology , Chlorocebus aethiops , Endosomes/chemistry , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins , Membrane Fusion , Vero Cells , Virus Replication
8.
Methods Mol Biol ; 2099: 9-20, 2020.
Article in English | MEDLINE | ID: covidwho-1292544

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonotic pathogen with a broad host range. The extent of MERS-CoV in nature can be traced to its adaptable cell entry steps. The virus can bind host-cell carbohydrates as well as proteinaceous receptors. Following receptor interaction, the virus can utilize diverse host proteases for cleavage activation of virus-host cell membrane fusion and subsequent genome delivery. The fusion and genome delivery steps can be completed at variable times and places, either at or near cell surfaces or deep within endosomes. Investigators focusing on the CoVs have developed several methodologies that effectively distinguish these different cell entry pathways. Here we describe these methods, highlighting virus-cell entry factors, entry inhibitors, and viral determinants that specify the cell entry routes. While the specific methods described herein were utilized to reveal MERS-CoV entry pathways, they are equally suited for other CoVs, as well as other protease-dependent viral species.


Subject(s)
Coronavirus Infections/virology , Genome, Viral/genetics , Middle East Respiratory Syndrome Coronavirus/physiology , Virus Internalization , Cell Membrane/virology , Endosomes/virology , HEK293 Cells , Humans , Membrane Proteins/metabolism , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Peptide Hydrolases/metabolism , RNA-Binding Proteins/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
9.
Cells ; 10(5)2021 05 07.
Article in English | MEDLINE | ID: covidwho-1223961

ABSTRACT

The flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19.


Subject(s)
COVID-19/drug therapy , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Flavanones/pharmacology , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Arabidopsis/metabolism , COVID-19/epidemiology , COVID-19/pathology , COVID-19/virology , Calcium Channel Blockers/therapeutic use , Drug Evaluation, Preclinical , Endosomes/drug effects , Endosomes/metabolism , Endosomes/virology , Flavanones/therapeutic use , Humans , Lysosomes/drug effects , Lysosomes/metabolism , Lysosomes/virology , Neoplasms/blood supply , Neoplasms/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Pandemics/prevention & control , SARS-CoV-2/pathogenicity , Vacuoles/metabolism , Virus Internalization/drug effects
10.
J Biol Chem ; 296: 100306, 2021.
Article in English | MEDLINE | ID: covidwho-1152462

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, so understanding its biology and infection mechanisms is critical to facing this major medical challenge. SARS-CoV-2 is known to use its spike glycoprotein to interact with the cell surface as a first step in the infection process. As for other coronaviruses, it is likely that SARS-CoV-2 next undergoes endocytosis, but whether or not this is required for infectivity and the precise endocytic mechanism used are unknown. Using purified spike glycoprotein and lentivirus pseudotyped with spike glycoprotein, a common model of SARS-CoV-2 infectivity, we now demonstrate that after engagement with the plasma membrane, SARS-CoV-2 undergoes rapid, clathrin-mediated endocytosis. This suggests that transfer of viral RNA to the cell cytosol occurs from the lumen of the endosomal system. Importantly, we further demonstrate that knockdown of clathrin heavy chain, which blocks clathrin-mediated endocytosis, reduces viral infectivity. These discoveries reveal that SARS-CoV-2 uses clathrin-mediated endocytosis to gain access into cells and suggests that this process is a key aspect of virus infectivity.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , Clathrin Heavy Chains/genetics , Endocytosis/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization/drug effects , A549 Cells , Angiotensin-Converting Enzyme 2/metabolism , Animals , Chlorocebus aethiops , Clathrin Heavy Chains/antagonists & inhibitors , Clathrin Heavy Chains/metabolism , Endocytosis/drug effects , Endosomes/drug effects , Endosomes/metabolism , Endosomes/virology , Gene Expression Regulation , Genetic Vectors/chemistry , Genetic Vectors/metabolism , HEK293 Cells , Host-Pathogen Interactions/genetics , Humans , Hydrazones/pharmacology , Lentivirus/genetics , Lentivirus/metabolism , Protein Binding/drug effects , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism , Sulfonamides/pharmacology , Thiazolidines/pharmacology , Vero Cells
11.
Nat Commun ; 12(1): 961, 2021 02 11.
Article in English | MEDLINE | ID: covidwho-1078585

ABSTRACT

The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.


Subject(s)
COVID-19/virology , CRISPR-Cas Systems , Genome-Wide Association Study , Host-Pathogen Interactions , SARS-CoV-2/physiology , Virus Internalization , A549 Cells , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/genetics , Chlorocebus aethiops , Disease Models, Animal , Endosomes/virology , HeLa Cells , Humans , Mesocricetus , Serine Endopeptidases , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
12.
Cell Calcium ; 94: 102360, 2021 03.
Article in English | MEDLINE | ID: covidwho-1064903

ABSTRACT

Ion channels are necessary for correct lysosomal function including degradation of cargoes originating from endocytosis. Almost all enveloped viruses, including coronaviruses (CoVs), enter host cells via endocytosis, and do not escape endosomal compartments into the cytoplasm (via fusion with the endolysosomal membrane) unless the virus-encoded envelope proteins are cleaved by lysosomal proteases. With the ongoing outbreak of severe acute respiratory syndrome (SARS)-CoV-2, endolysosomal two-pore channels represent an exciting and emerging target for antiviral therapies. This review focuses on the latest knowledge of the effects of lysosomal ion channels on the cellular entry and uncoating of enveloped viruses, which may aid in development of novel therapies against emerging infectious diseases such as SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/virology , Ion Channels/physiology , Lysosomes/virology , SARS-CoV-2/physiology , Viral Envelope/physiology , Virus Internalization , Virus Uncoating , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Antiviral Agents/pharmacology , Drug Design , Endocytosis , Endosomes/metabolism , Endosomes/virology , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Hydrazones/pharmacology , Hydrazones/therapeutic use , Ion Channels/classification , Lysosomes/enzymology , Lysosomes/metabolism , Models, Biological , Morpholines/pharmacology , Morpholines/therapeutic use , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Vacuolar Proton-Translocating ATPases/physiology , Virus Internalization/drug effects , Virus Uncoating/drug effects
14.
FEBS J ; 287(17): 3664-3671, 2020 09.
Article in English | MEDLINE | ID: covidwho-960850

ABSTRACT

The quest for the effective treatment against coronavirus disease 2019 pneumonia caused by the severe acute respiratory syndrome (SARS)-coronavirus 2(CoV-2) coronavirus is hampered by the lack of knowledge concerning the basic cell biology of the infection. Given that most viruses use endocytosis to enter the host cell, mechanistic investigation of SARS-CoV-2 infection needs to consider the diversity of endocytic pathways available for SARS-CoV-2 entry in the human lung epithelium. Taking advantage of the well-established methodology of membrane trafficking studies, this research direction allows for the rapid characterisation of the key cell biological mechanism(s) responsible for SARS-CoV-2 infection. Furthermore, 11 clinically approved generic drugs are identified as potential candidates for repurposing as blockers of several potential routes for SARS-CoV-2 endocytosis. More broadly, the paradigm of targeting a fundamental aspect of human cell biology to protect against infection may be advantageous in the context of future pandemic outbreaks.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Endocytosis/drug effects , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Amiloride/pharmacology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Caveolae/drug effects , Caveolae/virology , Chlorpromazine/pharmacology , Clathrin-Coated Vesicles/drug effects , Clathrin-Coated Vesicles/virology , Endosomes/drug effects , Endosomes/virology , Humans , Itraconazole/pharmacology , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/virology , Lysosomes/drug effects , Lysosomes/virology , Nystatin/pharmacology , Pinocytosis/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vinblastine/pharmacology
15.
Emerg Microbes Infect ; 9(1): 2245-2255, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-795734

ABSTRACT

The Coronavirus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2) is a global health emergency. As only very limited therapeutic options are clinically available, there is an urgent need for the rapid development of safe, effective, and globally available pharmaceuticals that inhibit SARS-CoV-2 entry and ameliorate COVID-19 severity. In this study, we explored the use of small compounds acting on the homeostasis of the endolysosomal host-pathogen interface, to fight SARS-CoV-2 infection. We find that fluoxetine, a widely used antidepressant and a functional inhibitor of acid sphingomyelinase (FIASMA), efficiently inhibited the entry and propagation of SARS-CoV-2 in the cell culture model without cytotoxic effects and also exerted potent antiviral activity against two currently circulating influenza A virus subtypes, an effect which was also observed upon treatment with the FIASMAs amiodarone and imipramine. Mechanistically, fluoxetine induced both impaired endolysosomal acidification and the accumulation of cholesterol within the endosomes. As the FIASMA group consists of a large number of small compounds that are well-tolerated and widely used for a broad range of clinical applications, exploring these licensed pharmaceuticals may offer a variety of promising antivirals for host-directed therapy to counteract enveloped viruses, including SARS-CoV-2.


Subject(s)
Antidepressive Agents/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/virology , Enzyme Inhibitors/pharmacology , Fluoxetine/pharmacology , Pneumonia, Viral/virology , Betacoronavirus/physiology , COVID-19 , Cell Line , Endosomes/virology , Humans , Pandemics , SARS-CoV-2 , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Virus Replication/drug effects
16.
Viruses ; 12(7)2020 07 03.
Article in English | MEDLINE | ID: covidwho-636175

ABSTRACT

Chikungunya virus (CHIKV) is an enveloped virus that enters host cells and transits within the endosomes before starting its replication cycle, the precise mechanism of which is yet to be elucidated. Endocytosis and endosome acidification inhibitors inhibit infection by CHIKV, murine leukemia virus (MLV), or SARS-coronavirus, indicating that these viral entries into host cells occur through endosomes and require endosome acidification. Although endosomal cathepsin B protease is necessary for MLV, Ebola virus, and SARS-CoV infections, its role in CHIKV infection is unknown. Our results revealed that endocytosis inhibitors attenuated CHIKV-pseudotyped MLV vector infection in 293T cells but not in TE671 cells. In contrast, macropinocytosis inhibitors attenuated CHIKV-pseudotyped MLV vector infection in TE671 cells but not in 293T cells, suggesting that CHIKV host cell entry occurs via endocytosis or macropinocytosis, depending on the cell lines used. Cathepsin B inhibitor and knockdown by an shRNA suppressed CHIKV-pseudotyped MLV vector infection both in 293T and TE671 cells. These results show that cathepsin B facilitates CHIKV infection regardless of the entry pathway.


Subject(s)
Cathepsin B/metabolism , Chikungunya Fever/pathology , Chikungunya virus/physiology , Viral Envelope Proteins/metabolism , Virus Internalization , Cathepsin B/antagonists & inhibitors , Cell Line, Tumor , Endocytosis/physiology , Endosomes/virology , HEK293 Cells , HeLa Cells , Humans , Leukemia Virus, Murine/physiology , Pinocytosis/physiology , RNA Interference , RNA, Small Interfering/genetics
17.
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
18.
Open Heart ; 7(1)2020 06.
Article in English | MEDLINE | ID: covidwho-595177

ABSTRACT

The high rate of thrombotic complications associated with COVID-19 seems likely to reflect viral infection of vascular endothelial cells, which express the ACE2 protein that enables SARS-CoV-2 to invade cells. Various proinflammatory stimuli can promote thrombosis by inducing luminal endothelial expression of tissue factor (TF), which interacts with circulating coagulation factor VII to trigger extrinsic coagulation. The signalling mechanism whereby these stimuli evoke TF expression entails activation of NADPH oxidase, upstream from activation of the NF-kappaB transcription factor that drives the induced transcription of the TF gene. When single-stranded RNA viruses are taken up into cellular endosomes, they stimulate endosomal formation and activation of NADPH oxidase complexes via RNA-responsive toll-like receptor 7. It is therefore proposed that SARS-CoV-2 infection of endothelial cells evokes the expression of TF which is contingent on endosomal NADPH oxidase activation. If this hypothesis is correct, hydroxychloroquine, spirulina (more specifically, its chromophore phycocyanobilin) and high-dose glycine may have practical potential for mitigating the elevated thrombotic risk associated with COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/virology , Endosomes/virology , Endothelial Cells/virology , NADPH Oxidases/metabolism , Pneumonia, Viral/virology , Thromboplastin/metabolism , Thrombosis/virology , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Blood Coagulation/drug effects , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Endosomes/drug effects , Endosomes/enzymology , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Enzyme Activation , Fibrinolytic Agents/therapeutic use , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , SARS-CoV-2 , Signal Transduction , Thrombosis/blood , Thrombosis/enzymology , Thrombosis/prevention & control
19.
FASEB J ; 34(6): 7253-7264, 2020 06.
Article in English | MEDLINE | ID: covidwho-175986

ABSTRACT

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.


Subject(s)
Antiviral Agents/pharmacokinetics , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Drug Repositioning , Endosomes/virology , Hydroxychloroquine/pharmacology , Lysosomes/virology , Niemann-Pick Disease, Type C/pathology , Pneumonia, Viral/drug therapy , ADAM17 Protein/physiology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Biological Transport , COVID-19 , Cathepsin L/physiology , Endocytosis , Endosomes/drug effects , Endosomes/physiology , Glycopeptides/pharmacology , Glycopeptides/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/physiology , Lysosomes/drug effects , Lysosomes/metabolism , Membrane Lipids/metabolism , Membrane Microdomains/physiology , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/metabolism , Oxysterols/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , SARS-CoV-2 , Serine Endopeptidases/physiology , Triazoles/pharmacology , Triazoles/therapeutic use , Virus Internalization/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL