In vitro effect of several antiviral drugs against various SARS-CoV-2 variants of concern

An independent study confirms that current and prospective antiviral treatments, including remdesivir and oral anew coronavirus disease 2019 (COVID-19) oral antiviral treatments Lagevrio (molnupiravir) Paxlovid (nirmatrelvir) are effective in inhibiting severe infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Image Credit: Naeblys/ShutterstockStudy: Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Image Credit: Naeblys/Shutterstock

In late December 2021, the U.S. Food & Drug Administration granted emergency use authorization for Paxlovid and Lagevrio for mild to moderate COVID-19 infection in adults. They also approved Paxlovid for children over the age of 12 who show a significant risk for life-threatening illness and hospitalization.

The research study, published in the bioRxiv* preprint server and awaiting peer review, found that the treatments retained their antiviral activity across several variants of concern, including Omicron.

Study details

The researchers exposed VeroE6-GFP cells to several antiviral COVID-19 treatments before infecting them with a viral isolate from five SARS-CoV-2 variants of concern. The SARS-CoV-2 ancestral strain was grown from the first Belgian patient sample. The researchers counted the number of fluorescent pixels from a GFP signal, determined by imaging after four days of infection. They measured the concentration of each drug at 50% efficacy for each variant.

The antiviral treatments studied were remdesivir, the oral analog of remdesivir GS-441524, the RNA polymerase inhibitors EIDD-1931 and Lagevrio, and the protease inhibitor Paxlovid.

One of the first COVID-19 treatments in pill form, Paxlovid works differently from COVID-19 vaccines because it targets the main protease rather than the spike protein, where most mutations from variants of concern reside. The main protease is a cysteine protease that cleaves two polyproteins of SARS-CoV-2 at various locations. Doing so produces a multitude of non-structural proteins essential for viral replication. Paxlovid is co-formulated with a low dose of ritonavir to protect against severe COVID-19 illness and hospitalization if taken within the first few days of symptoms.

As a protease inhibitor, Paxlovid stops viruses from replicating within cells, reducing the chances for the virus to spread throughout the body and cause severe illness.

Molnupiravir and EIDD-1931 were originally developed to prevent viral replication of other RNA viruses, including influenza. Recent clinical trial data of molnupirvair found the drug accelerates SARS-CoV-2 RNA clearance and shortens the elimination time of the virus.

Results

All antiviral COVID-19 treatments showed similar antiviral activity against current variants of concern — Alpha, Beta, Gamma, Delta, and Omicron. The researchers suggest this is likely because the proteins targeted by antivirals are not as many mutated proteins compared to other SARS-CoV-2 areas.

Although RNA polymerase had two amino acid changes — P313L in all variants of concern and G661S in Delta — compared to the original SARS-CoV-2 strain. For the SARS-CoV-2 protease, there were three amino acid mutations, including K90R in Alpha, P132H in Omicron, and V296I in Delta. However, neither mutations in RNA polymerase and SARS-CoV-2 protease were in the active site, creating no difference in susceptibility.

Given the consistent antiviral activity across variants, the results strongly suggest current COVID-19 treatments will remain effective against future SARS-CoV-2 variants. Beyond SARS-CoV-2, having broad-spectrum antiviral could help in mitigating the impact of future viral outbreaks.

“It is therefore important to continue both vaccine development as well as antiviral research, as they are both essential armor and complement each other in the strategy to control the current pandemic,” concluded the research team.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.

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