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Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication.

ABSTRACT: Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/β1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.

SUBMITTER: Low ZY

PROVIDER: S-EPMC8526435 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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Project description:New therapeutic targets are a valuable resource in the struggle to reduce the morbidity and mortality associated with the COVID-19 pandemic. Genome-wide association studies (GWAS) have identified a number of risk loci but these include co-morbidities and are not specific to host-virus interactions. Here, we identify and experimentally validate a link between reduced expression of EXOSC2 and reduced SARS-CoV-2 replication. We identified lung-specific eQTLs from GTEx (v7) for 332 host proteins which directly interact with SARS-CoV-2 proteins. Aggregating COVID-19 GWAS statistics for gene-specific eQTLs revealed a robust association between increased expression of EXOSC2 and higher risk of clinical COVID-19. EXOSC2 is a component of the RNA exosome and further LC-MS/MS analysis of protein pulldowns demonstrated an interaction between the SARS-CoV-2 RNA polymerase and the majority of RNA exosome components. CRISPR/Cas9 introduction of nonsense mutations within EXOSC2 in Calu3 cells reduced EXOSC2 protein expression, impeded SARS-CoV-2 replication and upregulated OAS genes which have been linked to a successful immune response against SARS-CoV-2. OAS gene expression changes occurred independent of infection, in the absence of significant upregulation of other interferon-stimulated genes (ISGs), and did not coincide with reduced cellular viability. Targeted depletion or functional inhibition of EXOSC2 may be a safe and effective strategy to protect at-risk individuals against clinical COVID-19.

2022-10-13 | PXD031611 | Pride

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