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Pharmacologic profiling reveals lapatinib as a novel antiviral against SARS-CoV-2 in vitro.

ABSTRACT: The emergence of SARS-CoV-2 virus has resulted in a worldwide pandemic, but effective antiviral therapies are not widely available. To improve treatment options, we conducted a high-throughput screen to uncover compounds that block SARS-CoV-2 infection. A minimally pathogenic human betacoronavirus (OC43) was used to infect physiologically-relevant human pulmonary fibroblasts (MRC5) to facilitate rapid antiviral discovery in a preclinical model. Comprehensive profiling was conducted on more than 600 compounds, with each compound arrayed across 10 dose points. Our screening revealed several FDA-approved agents that can attenuate both OC43 and SARS-CoV-2 viral replication, including lapatinib, doramapimod, and 17-AAG. Importantly, lapatinib inhibited SARS-CoV-2 RNA replication by over 50,000-fold. Further, both lapatinib and doramapimod could be combined with remdesivir to improve antiviral activity in cells. These findings reveal novel therapeutic avenues that could limit SARS-CoV-2 infection.

SUBMITTER: Raymonda MH

PROVIDER: S-EPMC8626825 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The novel SARS-CoV-2 variants of concern (VOC) represent a considerable global alarm because their mutations are known to affect transmissibility and cause immune escape. While preventing severe disease and deaths, the available vaccines do not avoid infection; therefore, COVID-19 disease management still requires effective therapies. We have recently reported that the aminothiol cysteamine, a drug already applied to humans, exerts direct antiviral activity against SARS-CoV-2 and has in vitro immunomodulatory effect. To evaluate whether this compound exerts antiviral effects also against SARS-CoV-2 variants, we performed different infected cell-based assays using Wild type, Delta, or Omicron VOC. We found that cysteamine significantly reduces the cytopathic effect induced by SARS-CoV-2 Wild type strain and Delta variant in Vero E6 cells. On the other hand, cysteamine had no effects on the survival of cells infected with the Omicron variant, due to the lack of cytotoxicity on Vero E6 cells, at least when infected at MOI = 0.001 for 72 h. Moreover, cysteamine significantly reduced the production of Wild type, Delta, and Omicron variants as measured by the virus released in the culture media (Vero E6 and Calu-3 cells) and by transmission electron microscopy analysis (Vero E6 cells). Notably, cysteamine is more effective in inhibiting the Omicron rather than Delta or Wild type viruses, with an 80% inhibition of Omicron production compared to 40% of Wild type and Delta variant. Overall, our findings demonstrate that cysteamine exerts direct antiviral actions against SARS-CoV-2 Delta and Omicron variants, in addition to the Wild type virus. Our data further demonstrate that cysteamine is a good candidate as repurposing drug for the treatment of SARS-CoV-2 infection for the present and, likely, the future VOC and, therefore, it would be important to investigate its clinical relevance in randomized clinical trials.

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Project description:The coronavirus disease (COVID-19), caused by the virus SARS-CoV-2, has become a global pandemic in a very short time span. While several vaccines have been developed in the last year, specific treatments for CoV infection are still being explored. Thus, the situation highlights the need to develop safe and efficacious antiviral therapeutics. Ayurvedic Rasayana therapy has been traditionally used in India for its holistic healing systems and proven history of empirical use. There is emerging evidence that Ayurvedic treatment methodologies and herbal medicines may be effective strategies in combating COVID-19. The present study is aimed at evaluating the antiviral and therapeutic activity of an Ayurvedic herbomineral formulation (Svarnvir-IV tablet, 450 mg) against the SARS-CoV-2 virus in vitro. A cell-based assay was conducted to evaluate the cytotoxicity of the Svarnvir-IV tablets (Aimil Pharmaceuticals, Delhi, India) for the determination of virucidal activity assessment (at 2 hours) and therapeutic activity assessment (at 1 hour, 2 hours, and 4 hours). When incubated with SARS-CoV-2 virus at 0.1 multiplicity of infection (MoI) for two hours, Svarnvir-IV tablet exhibited virucidal activity against SARS-CoV-2 with an EC50 value of 0.0058 mg/ml. It also exhibited therapeutic activity when treated with cells infected with the SARS-CoV-2 virus (0.1 MoI) for 1 hour, 2 hours and 4 hours post-infection, with an EC50 value of 0.094 mg/ml, 0.023 mg/ml, and 0.05 mg/ml, respectively. The original supporting data obtained from this study, along with existing Ayurvedic traditional information, has shown encouraging results.

| S-EPMC10288389 | biostudies-literature

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