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Lifeline Cells Continue to Aid COVID-19 Research

2020 was a year of uncertainty and unprecedented change brought on by the emergence of the SARS-CoV-2 virus and COVID-19 disease, which has impacted the lives of so many people worldwide. Since the start of the global pandemic, researchers and clinicians have worked tirelessly towards an effective COVID-19 vaccine and the much-anticipated news of several vaccine approvals by the FDA brings hope for a return to some normalcy in 2021.

Currently, there are two COVID-19 vaccines approved by the FDA for emergency use being distributed and administered to the population:

  • Pfizer/BioNTech COVID-19 Vaccine
  • Moderna COVID-19 Vaccine

A third vaccine by Oxford/AstraZeneca has been approved in the UK and is pending approval in other countries such as India and the US. As evidenced by the speed at which the COVID-19 vaccines came about, we need to support the efforts of the global scientific community now, more than ever, to develop more life-saving technologies.

In parallel to the vaccine development efforts, researchers were actively seeking therapeutic treatments for patients already infected and hospitalized with SARS-CoV-2. Gilead’s remdesivir (RDV, GS-5734) was shown to have efficacy as a COVID-19 treatment and is currently FDA-approved for COVID-19 patients requiring hospitalization. RDV is an antiviral with broad-spectrum activity against members of the coronavirus family such as SARS-CoV-2, SARS-CoV, and MERS-CoV. However, since it was initially designed by scientists to treat Ebola, researchers are assessing the potential off-target cytotoxicity that could be associated with RDV treatment.

Defining the Safety Profile of Remdesivir using Lifeline Cells

RDV is a direct-acting antiviral acting as a nucleoside analog, which mimics the naturally-occurring nucleoside, adenosine. It works by blocking the coronavirus’s RNA polymerase, a key enzyme needed for the virus to replicate its genetic material (RNA). When the polymerase incorporates this nucleoside analog rather than the natural molecule, viral replication is inhibited, preventing the virus from proliferating and infecting more cells in the body.

RDV is classified as a “prodrug,” meaning it needs modification in the body before it becomes an active drug. The conversion into its active triphosphate form (recognized by viral RNA polymerase) produces metabolites that may have an adverse effect on cellular processes. In a recent publication by Xu and Colleagues, Lifeline’s Normal Human Renal Proximal Tubule Cells (RPTEC’s) were used along with other relevant human primary cells and immortalized cell lines to evaluate off-target toxicities associated with the drug and its metabolites including parent nucleoside analog (GS-441524), intermediate metabolite MetX (GS-704277), and the active triphosphate metabolite (GS-443902) using a series of cellular and biochemical assays. Because the kidneys are major clearance organs of the body to eliminate many xenobiotics and prescription drugs, RPTEC’s serve as excellent in vitro models to evaluate drug cytotoxicity.

The authors sought to define the drug safety profile of RDV and its metabolites by looking at general cytotoxicity, measured as CC50 (concentration necessary to kill 50% of the host cells), after 5-14 days of exposure to the drug. As well, to understand whether the cytotoxicity is associated with the mitochondria specifically, they measured the effects on mitochondrial DNA content, mitochondrial protein synthesis, cellular respiration, and induction of reactive oxygen species (ROS) under aerobic and anaerobic metabolic conditions.

After 5-14 days of continuous exposure to RDV, the CC50 values ranged from 1.7 to > 20 μM, resulting in selectivity indices (SI) from >170 to 20,000. The higher the SI ratio, the safer and more effective a drug is to treat an in vivo viral infection. In contrast, the IC50 (concentration needed to inhibit the 50% of the virus) of RDV with respect to its anti-SARS-CoV-2 activity is very low at only 9.9 nM in human airway epithelial cells. Additionally, results indicate both the parent nucleoside and the major systemic metabolites showed less cytotoxicity than RDV. Of note, however, and consistent with clinical observations reporting elevated liver enzyme values with repeated RDV exposure, primary hepatocytes showed a high in vitro susceptibility to the drug. The authors postulate this could be due to the high cellular permeability and efficient intracellular metabolism by liver enzymes in converting RDV to its active triphosphate form. Mitochondrial-specific assays determined that RDV and its active metabolite did not show specific inhibition for mitochondrial DNA or RNA polymerase. Furthermore, neither RDV nor its systemic metabolites induced ROS formation in vitro.

Taken together, Xu and Colleagues concluded that RDV has a low potential for the off-target toxicities, which is commonly observed with other nucleoside analogs including mitochondrial toxicity. In clinical settings where RDV is used for COVID-19 treatment, the risk associated with possible RDV side effects is far outweighed by the established benefits for hospitalized patients.

For more information on Lifeline’s cells and media products, please visit https://www.lifelinecelltech.com/

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