Anti-Parasitic Drug, Ivermectin Shows Anti-COVID-19 Ability in The Lab

By Sahana Shankar, Ph.D. Candidate

Investigators from Monash University’s Biomedicine Discovery Institute (BDI) and the Peter Doherty Institute of Infection and Immunity, Melbourne, Australia test the FDA-approved anti-parasitic ivermectin as an inhibitor against SARS-CoV2 growth in vitro and demonstrate promising results.

Scientists all around the world are racing against time to find a panacea for the COVID-19 pandemic that has ravaged the lives and livelihoods of millions globally. The current therapeutic approach is restricted to containment and monitoring of infected patients, supplemented with respiratory assistance in critical cases. This is due to the novelty of the virus and our relative inexperience with it. Vaccine developments are underway in multiple countries funded by private and public institutions. However, validation and approval of a vaccine for human use is a time-consuming process. Another concern would be the rapid scale-up of vaccine production and distribution.

An alternate approach is to screen known drugs with anti-viral properties and test their efficacy to inhibit the causative virus, SARS-CoV-2. Among the several drugs repurposed to treat COVID-19, Gilead Sciences’ remdesivir, originally designed for Ebola, is a major candidate that is under trials as a potential COVID-19 therapy. In the same vein, scientists from Australia have now reported that within 48 hours, a known antiparasitic drug, ivermectin can effectively kill SARS-CoV-2 viruses in Vero/hSLAM cells, a lab-grown cell line popular as a viral disease model.

Viruses gain entry into the host cell by binding to a cell surface receptor. The ability to cause disease depends on the robustness in which the viral genome replicates inside the host cell nucleus. If the viral genome and/or accessory proteins cannot reach the nucleus, it cannot hijack the host cell to replicate and infect nearby cells. This also elicits a robust antiviral response from the host immune system. Most proteins need a chaperone to cross the nuclear membrane. In animal cells, Importins are an essential family of chaperones that regulate the movement of proteins in and out of the nucleus as and when required.

Ivermectin, an FDA-Approved Anti-Parasitic

Ivermectin is an FDA-approved anti-parasitic drug used to kill intestinal nematodes. It is also known to be effective against a broad spectrum of viruses including HIV-1, SV40, dengue virus, West Nile virus, Venezuelan equine encephalitis virus and influenza virus. The mode of action of ivermectin is inhibition of nuclear import of both host and viral proteins. It was originally identified as the drug that inhibited the binding of HIV-integrase protein with host Importin α/β. The collaborative study conducted by scientists from Monash University’s Biomedicine Discovery Institute (BDI) and the Peter Doherty Institute of Infection and Immunity in Melbourne zeroed in on ivermectin as a potential SARS-CoV-2 inhibitor because:

• It is a known inhibitor of nuclear import in several RNA viral infections (SARS-CoV-2 is an RNA virus)
• Previous studies of SARS patients showed that nuclear transport of the SARS-CoV nucleocapsid protein (important for viral packaging) is dependent on Importin α/β
• Imp α/β inhibition is also implicated in host antiviral response via the STAT1 pathway

Results of the New Study

The team infected the Vero/hSLAM cells with the SARS-CoV-2 virus isolated from a patient in Australia. The cell pellets and supernatant were tested for a quantitative measure of viral proliferation by RT-PCR. At 24h after infection, there was a 93% reduction of viral RNA in the supernatant, indicating that the virus was unable to release packaged virions into the medium and 99.8% elimination of viral RNA in cell pellets, suggesting that there were no remnants of unpackaged viral particles in the cells. At 48h, there was 99.8% elimination of viral RNA in infected cells compared to control cells. In cells dosed with serial dilutions of ivermectin 2h post-infection, there was a ~5000-fold reduction in viral RNA. The results were replicated in RT-PCR with both the viral RdRp and E genes, suggesting that ivermectin has an efficient antiviral activity specifically against SARS-CoV-2 in vitro. Further studies shall focus on elucidating the mechanism of nuclear import inhibition by ivermectin.

Study lead Kylie Wagstaff and co-author David Jans identified the antiviral activity of ivermectin back in the year 2012. “In times when we’re having a global pandemic and there isn’t an approved treatment, if we had a compound that was already available around the world then that might help people sooner,” said Wagstaff, who began the study as soon as news of the COVID-19 pandemic broke. Lead author, Dr. Leon Caly is “the virologist who was part of the team who were first to isolate and share SARS-CoV-2 outside of China in January 2020”. He is “excited about the prospect of ivermectin being used as a potential drug against COVID-19”.

The team suggests that ivermectin could be administered in early infection to restrict viral replication and disease progression. It can serve as a benchmark for screening potential antivirals for SARS-CoV-2. Further preclinical and clinical trials are needed to check (a) its ability to prevent and/or reduce the severity/time of SARS-CoV-2 infection in humans (b) effective dosage in patients. Since ivermectin is an FDA-approved drug, already on the WHO list of essential medicines and has an established clinical safety profile, it can be quickly repurposed as a COVID-19 drug.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: COVID-19 Victims on Remdesivir Treatment Hopeful after First US Patient Recovers

References

1. https://www.gilead.com/purpose/advancing-global-health/covid-19/remdesivir-clinical-trials
2. https://www.sciencedirect.com/science/article/pii/S0166354220302011

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Author

Sahana Shankar