Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Sci Rep ; 12(1): 5758, 2022 04 06.
Article in English | MEDLINE | ID: covidwho-1778630

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of the COVID-19 pandemic. More than 274 million individuals have suffered from COVID-19 and over five million people have died from this disease so far. Therefore, there is an urgent need for therapeutic drugs. Repurposing FDA approved drugs should be favored since evaluation of safety and efficacy of de-novo drug design are both costly and time consuming. We report that imatinib, an Abl tyrosine kinase inhibitor, robustly decreases SARS-CoV-2 infection and uncover a mechanism of action. We show that imatinib inhibits the infection of SARS-CoV-2 and its surrogate lentivector pseudotype. In latter, imatinib inhibited both routes of viral entry, endocytosis and membrane-fusion. We utilized a system to quantify in real-time cell-cell membrane fusion mediated by the SARS-CoV-2 surface protein, Spike, and its receptor, hACE2, to demonstrate that imatinib inhibits this process in an Abl1 and Abl2 independent manner. Furthermore, cellular thermal shift assay revealed a direct imatinib-Spike interaction that affects Spike susceptibility to trypsin digest. Collectively, our data suggest that imatinib inhibits Spike mediated viral entry by an off-target mechanism. These findings mark imatinib as a promising therapeutic drug in inhibiting the early steps of SARS-CoV-2 infection.


Subject(s)
COVID-19 , COVID-19/drug therapy , Humans , Imatinib Mesylate/pharmacology , Pandemics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization
2.
Cell Metab ; 34(3): 424-440.e7, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1676683

ABSTRACT

Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.


Subject(s)
COVID-19/drug therapy , Imatinib Mesylate/therapeutic use , Metabolic Diseases/drug therapy , Methazolamide/therapeutic use , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , Chlorocebus aethiops , Down-Regulation/drug effects , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Imatinib Mesylate/pharmacology , Male , Metabolic Diseases/metabolism , Metabolic Diseases/virology , Methazolamide/pharmacology , Mice , Mice, Inbred C57BL , Mice, Obese , Mice, Transgenic , SARS-CoV-2/physiology , Vero Cells , Virus Internalization/drug effects
3.
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
4.
Int J Biol Macromol ; 190: 636-648, 2021 Nov 01.
Article in English | MEDLINE | ID: covidwho-1401500

ABSTRACT

SARS-CoV-2 nucleocapsid (N) protein undergoes RNA-induced phase separation (LLPS) and sequesters the host key stress granule (SG) proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and 2 (G3BP1 and G3BP2) to inhibit SG formation. This will allow viral packaging and propagation in host cells. Based on a genomic-guided meta-analysis, here we identify upstream regulatory elements modulating the expression of G3BP1 and G3BP2 (collectively called G3BP1/2). Using this strategy, we have identified FOXA1, YY1, SYK, E2F-1, and TGFBR2 as activators and SIN3A, SRF, and AKT-1 as repressors of G3BP1/2 genes. Panels of the activators and repressors were then used to identify drugs that change their gene expression signatures. Two drugs, imatinib, and decitabine have been identified as putative modulators of G3BP1/2 genes and their regulators, suggesting their role as COVID-19 mitigation agents. Molecular docking analysis suggests that both drugs bind to G3BP1/2 with a much higher affinity than the SARS-CoV-2 N protein. This study reports imatinib and decitabine as candidate drugs against N protein and G3BP1/2 protein.


Subject(s)
Adaptor Proteins, Signal Transducing/chemistry , COVID-19/drug therapy , Coronavirus Nucleocapsid Proteins/chemistry , DNA Helicases/chemistry , Decitabine/chemistry , Imatinib Mesylate/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Poly-ADP-Ribose Binding Proteins/chemistry , RNA Helicases/chemistry , RNA Recognition Motif Proteins/chemistry , RNA-Binding Proteins/chemistry , SARS-CoV-2/chemistry , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/metabolism , COVID-19/metabolism , Coronavirus Nucleocapsid Proteins/metabolism , DNA Helicases/antagonists & inhibitors , DNA Helicases/metabolism , Decitabine/pharmacology , Drug Delivery Systems , Genomics , Imatinib Mesylate/pharmacology , Phosphoproteins/chemistry , Phosphoproteins/metabolism , Poly-ADP-Ribose Binding Proteins/antagonists & inhibitors , Poly-ADP-Ribose Binding Proteins/metabolism , RNA Helicases/antagonists & inhibitors , RNA Helicases/metabolism , RNA Recognition Motif Proteins/antagonists & inhibitors , RNA Recognition Motif Proteins/metabolism , RNA-Binding Proteins/antagonists & inhibitors , RNA-Binding Proteins/metabolism , SARS-CoV-2/metabolism
6.
Antiviral Res ; 193: 105137, 2021 09.
Article in English | MEDLINE | ID: covidwho-1306846

ABSTRACT

Following the emergence of SARS-CoV-2, the search for an effective and rapidly available treatment was initiated worldwide based on repurposing of available drugs. Previous reports described the antiviral activity of certain tyrosine kinase inhibitors (TKIs) targeting the Abelson kinase 2 against pathogenic coronaviruses. Imatinib, one of them, has more than twenty years of safe utilization for the treatment of hematological malignancies. In this context, Imatinib was rapidly evaluated in clinical trials against Covid-19. Here, we present the pre-clinical evaluation of imatinib in multiple models. Our results indicated that imatinib and another TKI, the masitinib, exhibit an antiviral activity in VeroE6 cells. However, imatinib was inactive in a reconstructed bronchial human airway epithelium model. In vivo, imatinib therapy failed to impair SARS-CoV-2 replication in a golden Syrian hamster model despite high concentrations in plasma and in the lung. Overall, these results do not support the use of imatinib and similar TKIs as antivirals in the treatment of Covid-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Imatinib Mesylate/pharmacology , SARS-CoV-2/drug effects , Animals , COVID-19/epidemiology , COVID-19/virology , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Drug Repositioning , Enzyme Inhibitors/pharmacology , Epithelium , Female , Humans , Lung/pathology , Male , Mesocricetus , Vero Cells , Virus Replication/drug effects
7.
Int J Mol Sci ; 22(13)2021 Jun 28.
Article in English | MEDLINE | ID: covidwho-1288900

ABSTRACT

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Down-Regulation/drug effects , Imatinib Mesylate/pharmacology , SARS-CoV-2/physiology , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Animals , COVID-19/pathology , COVID-19/virology , Cell Line , Cell Survival/drug effects , Chlorocebus aethiops , Female , Genes, Reporter , Humans , Mice , Promoter Regions, Genetic , SARS-CoV-2/isolation & purification
8.
Phys Chem Chem Phys ; 23(22): 12549-12558, 2021 Jun 09.
Article in English | MEDLINE | ID: covidwho-1233727

ABSTRACT

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell after the receptor binding domain (RBD) of the virus spike (S) glycoprotein binds to the human angiotensin-converting enzyme 2 (hACE2). This binding requires the RBD to undergo a conformational change from a closed to an open state. In the present study, a key pair of salt bridges formed by the side chains of K537 and E619, residues at the interfaces of SD1 and SD2, respectively, was identified to promote the opening of the RBD. Mutations of K537Q and E619D reduced their side chain lengths and eliminated this pair of salt bridges; as a result, the opening of the RBD was not observed in the MD simulations. Thus, blocking the formation of this pair of salt bridges is a promising approach for treating novel coronavirus disease 2019 (COVID-19). FDA approved drug molecules were screened by their capabilities of blocking the formation of the key pair of salt bridges, achieved by their positional stabilities in the cavity containing the side chains of K537 and E619 formed in the interface between SD1 and SD2. Simeprevir, imatinib, and naldemedine were identified to possess the desired capability with the most favorable interaction energies.


Subject(s)
Antiviral Agents/pharmacology , Drug Design , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Antiviral Agents/chemistry , Drug Evaluation, Preclinical , Humans , Imatinib Mesylate/chemistry , Imatinib Mesylate/pharmacology , Molecular Docking Simulation , Naltrexone/analogs & derivatives , Naltrexone/chemistry , Naltrexone/pharmacology , Protein Domains/drug effects , SARS-CoV-2/chemistry , Simeprevir/chemistry , Simeprevir/pharmacology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
9.
Basic Clin Pharmacol Toxicol ; 128(4): 621-624, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-965811

ABSTRACT

Since the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019, no vaccine has been approved to counter this infection and the available treatments are mainly directed against the immune pathology caused by the infection. The coronavirus disease 2019 (COVID-19) is currently causing a worldwide pandemic, pointing the urgent need for effective treatment. In such emergency, drug repurposing presents the best option for a rapid antiviral response. We assess here the in vitro activity of nilotinib, imatinib and dasatinib, three Abl tyrosine kinase inhibitors, against SARS-CoV-2. Although the last two compounds do not show antiviral efficacy, we observe inhibition with nilotinib in Vero-E6 cells and Calu-3 cells with EC50s of 1.44 µM and 3.06 µM, respectively. These values are close to the mean peak concentration of nilotinib observed at steady state in serum, making this compound a potential candidate for treatment of COVID-19 in vivo.


Subject(s)
Antiviral Agents/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , SARS-CoV-2/drug effects , Animals , Cell Line , Chlorocebus aethiops , Dasatinib/pharmacology , Dose-Response Relationship, Drug , Humans , Imatinib Mesylate/pharmacology , In Vitro Techniques , Vero Cells/virology
10.
Cell Death Dis ; 11(8): 656, 2020 08 19.
Article in English | MEDLINE | ID: covidwho-725491

ABSTRACT

The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act on-target, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their 'official' pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/metabolism , Drug Evaluation, Preclinical/methods , Pneumonia, Viral/metabolism , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacology , COVID-19 , Cell Death/drug effects , Chlorocebus aethiops , Coronavirus Infections/virology , Hydroxychloroquine/pharmacology , Imatinib Mesylate/pharmacology , Lysosomes/drug effects , Pandemics , Pneumonia, Viral/virology , Protein Kinase Inhibitors/pharmacology , RNA, Viral/drug effects , SARS-CoV-2 , Vero Cells , Viral Load/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL