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Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry.

ABSTRACT: Hydroxychloroquine (HCQ) has been proposed in the treatment of SARS-coronavirus 2 (SARS-CoV-2) infection, albeit with much controversy. In vitro, HCQ effectively inhibits viral entry, but its use in the clinic has been hampered by conflicting results. A better understanding of HCQ's mechanism of actions in vitro is needed to resolve these conflicts. Recently, anesthetics were shown to disrupt ordered monosialotetrahexosylganglioside1 (GM1) lipid rafts. These same lipid rafts recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to an endocytic entry point, away from phosphatidylinositol 4,5 bisphosphate (PIP₂) domains. Here we employed super resolution imaging of cultured mammalian cells to show HCQ directly perturbs GM1 lipid rafts and inhibits the ability of ACE2 receptor to associate with the endocytic pathway. HCQ also disrupts PIP₂ domains and their ability to cluster and sequester ACE2. Similarly, the antibiotic erythromycin inhibits viral entry and both HCQ and erythromycin decrease the antimicrobial host defense peptide amyloid beta in cultured cells. We conclude HCQ is an anesthetic-like compound that disrupts GM1 lipid rafts similar to anesthetics. The disruption likely decreases viral clustering at both endocytic and putative PIP₂ entry points.

SUBMITTER: Yuan Z

PROVIDER: S-EPMC7430563 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hydroxychloroquine in COVID-19: Potential Mechanism of Action Against SARS-CoV-2.

Project description:Purpose of Review:The rapid spread of virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned out to be a global emergency. Symptoms of this viral infection, coronavirus disease 2019 (COVID-19), include mild infections of the upper respiratory tract, viral pneumonia, respiratory failure, multiple organ failure and death. Till date, no drugs have been discovered to treat COVID-19 patients, and therefore, a considerable amount of interest has been shown in repurposing the existing drugs. Recent Findings:Out of these drugs, chloroquine (CQ) and hydroxychloroquine (HCQ) have demonstrated positive results indicating a potential antiviral role against SARS-CoV-2. Its mechanism of action (MOA) includes the interference in the endocytic pathway, blockade of sialic acid receptors, restriction of pH mediated spike (S) protein cleavage at the angiotensin-converting enzyme 2 (ACE2) binding site and prevention of cytokine storm. Unfortunately, its adverse effects like gastrointestinal complications, retinopathy and QT interval prolongation are evident in treated COVID-19 patients. Yet, multiple clinical trials have been employed in several countries to evaluate its ability in turning into a needed drug in this pandemic. Summary:This review attempts to summarize the MOA of CQ/HCQ and its side effects. The existing literature hints that till date, the role of CQ/HCQ in COVID-19 may be sceptical, and further studies are warranted for obtaining a therapeutic option that could be effectively used across the world to rise out from this pandemic.

| S-EPMC7443392 | biostudies-literature

Targeting spike glycans to inhibit SARS-CoV2 viral entry.

Project description:SARS-CoV-2 spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical approaches, we demonstrate that the interaction is avidity driven and that BOA cross-links the spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that multivalent glycan-targeting molecules have the potential to act as pan-coronavirus inhibitors.

| S-EPMC10515186 | biostudies-literature

Targeting Spike Glycans to Inhibit SARS-CoV2 Viral Entry.

Project description:SARS-CoV-2 Spike harbors glycans which function as ligands for lectins. Therefore, it should be possible to exploit lectins to target SARS-CoV-2 and inhibit cellular entry by binding glycans on the Spike protein. Burkholderia oklahomensis agglutinin (BOA) is an antiviral lectin that interacts with viral glycoproteins via N-linked high mannose glycans. Here, we show that BOA binds to the Spike protein and is a potent inhibitor of SARS-CoV-2 viral entry at nanomolar concentrations. Using a variety of biophysical tools, we demonstrate that the interaction is avidity driven and that BOA crosslinks the Spike protein into soluble aggregates. Furthermore, using virus neutralization assays, we demonstrate that BOA effectively inhibits all tested variants of concern as well as SARS-CoV 2003, establishing that glycan-targeting molecules have the potential to be pan-coronavirus inhibitors.

| S-EPMC9810211 | biostudies-literature

Approach to the mechanism of action of hydroxychloroquine on SARS-CoV-2: a molecular docking study.

Project description:We aimed to analyze the interactions of both hydroxychloroquine and chloroquine with SARS-CoV-2 and identify their possible role for the prevention/treatment of COVID-19 by molecular docking studies. Protein crystal structures of SARS-CoV-2 and ACE2, the compounds hydroxychloroquine and chloroquine, and other ligand structures were minimized by OPLS3 force field. Glide Standard Precision and Extra Precision docking are performed and MM-GBSA values are calculated. Molecular docking studies showed that hydroxychloroquine and chloroquine do not interact with SARS-CoV-2 proteins, but bind to the amino acids ASP350, ASP382, ALA348, PHE40 and PHE390 on the ACE2 allosteric site rather than the ACE2 active site. Our results showed that neither hydroxychloroquine and chloroquine bind to the active site of ACE2. However, both molecules prevent the binding of SARS-CoV-2 spike protein to ACE2 by interacting with the allosteric site. This result can help ACE2 inhibitor drug development studies to prevent viruses entering the cell by attaching spike protein to ACE2. Communicated by Ramaswamy H. Sarma.

| S-EPMC7441757 | biostudies-literature

Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2.

Project description:Hydroxychloroquine, used to treat malaria and some autoimmune disorders, potently inhibits viral infection of SARS coronavirus (SARS-CoV-1) and SARS-CoV-2 in cell-culture studies. However, human clinical trials of hydroxychloroquine failed to establish its usefulness as treatment for COVID-19. This compound is known to interfere with endosomal acidification necessary to the proteolytic activity of cathepsins. Following receptor binding and endocytosis, cathepsin L can cleave the SARS-CoV-1 and SARS-CoV-2 spike (S) proteins, thereby activating membrane fusion for cell entry. The plasma membrane-associated protease TMPRSS2 can similarly cleave these S proteins and activate viral entry at the cell surface. Here we show that the SARS-CoV-2 entry process is more dependent than that of SARS-CoV-1 on TMPRSS2 expression. This difference can be reversed when the furin-cleavage site of the SARS-CoV-2 S protein is ablated or when it is introduced into the SARS-CoV-1 S protein. We also show that hydroxychloroquine efficiently blocks viral entry mediated by cathepsin L, but not by TMPRSS2, and that a combination of hydroxychloroquine and a clinically-tested TMPRSS2 inhibitor prevents SARS-CoV-2 infection more potently than either drug alone. These studies identify functional differences between SARS-CoV-1 and -2 entry processes, and provide a mechanistic explanation for the limited in vivo utility of hydroxychloroquine as a treatment for COVID-19.

| S-EPMC7845965 | biostudies-literature

Clinical HDAC Inhibitors Are Effective Drugs to Prevent the Entry of SARS-CoV2.

Project description:The outbreak of COVID-19 by the end of 2019 has posed serious health threats to humanity and jeopardized the global economy. However, no effective drugs are available to treat COVID-19 currently and there is a great demand to fight against it. Here, we combined computational screening and an efficient cellular pseudotyped virus system, confirming that clinical HDAC inhibitors can efficiently prevent SARS-CoV-2 and potentially be used to fight against COVID-19.

| S-EPMC7671100 | biostudies-literature

Sars-cov2

Project description:Samples of Rio of Janeiro Maré , Brazil

| PRJEB43953 | ENA

Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection.

Project description:The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.

| S-EPMC7128678 | biostudies-literature

High expression of SARS-CoV2 viral entry-related proteins in human limbal stem cells.

Project description:PurposeCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). While the ocular surface is considered one of the major SARS-CoV2 transmission routes, the specific cellular tropism of SARS-CoV2 is not fully understood. In the current study, we evaluated the expression and regulation of two SARS-CoV2 viral entry proteins, TMPRSS2 and ACE2, in human ocular epithelial cells and stem cells.MethodsTMPRSS2 and ACE2 expression in ABCB5-positive limbal stem cells (LSCs) were assessed by RNAseq, flow cytometry and immunohistochemistry. PAX6, TMPRSS2, and ACE2 mRNA expression values were obtained from the GSE135455 and DRA002960 RNA-seq datasets. siRNA-mediated PAX6 knockdown (KD) was performed in limbal and conjunctival epithelial cells. TMPRSS2 and ACE2 expression in the PAX6 KD cells was analyzed by qRT-PCR and Western blot.ResultsWe found that ABCB5-positive LSCs express high levels of TMPRSS2 and ACE2 compared to ABCB5-negative limbal epithelial cells. Mechanistically, gene knockout and overexpression models revealed that the eye transcription factor PAX6 negatively regulates TMPRSS2 expression. Therefore, low levels of PAX6 in ABCB5-positive LSCs promote TMPRSS2 expression, and high levels of TMPRSS2 and ACE2 expression by LSCs indicate enhanced susceptibility to SARS-CoV2 infection in this stem cell population.ConclusionsOur study points to a need for COVID-19 testing of LSCs derived from donor corneas before transplantation to patients with limbal stem cell deficiency. Furthermore, our findings suggest that expandable human ABCB5+ LSC cultures might represent a relevant novel model system for studying cellular SARS-CoV2 viral entry mechanisms and evaluating related targeting strategies.

| S-EPMC8511872 | biostudies-literature

Molecular mechanism of anti-SARS-CoV2 activity of Ashwagandha-derived withanolides.

Project description:COVID-19 caused by SARS-CoV-2 corona virus has become a global pandemic. In the absence of drugs and vaccine, and premises of time, efforts and cost required for their development, natural resources such as herbs are anticipated to provide some help and may also offer a promising resource for drug development. Here, we have investigated the therapeutic prospective of Ashwagandha for the COVID-19 pandemic. Nine withanolides were tested in silico for their potential to target and inhibit (i) cell surface receptor protein (TMPRSS2) that is required for entry of virus to host cells and (ii) viral protein (the main protease Mpro) that is essential for virus replication. We report that the withanolides possess capacity to inhibit the activity of TMPRSS2 and Mpro. Furthermore, withanolide-treated cells showed downregulation of TMPRSS2 expression and inhibition of SARS-CoV-2 replication in vitro, suggesting that Ashwagandha may provide a useful resource for COVID-19 treatment.

| S-EPMC8188803 | biostudies-literature

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