An orally bioavailable prodrug called EIDD-2801 (β-D-N4-hydroxycytidine-5’-isopropyl ester) has broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic coronaviruses in primary human airway epithelial cells, according to a new study published in the journal Science Translational Medicine. The study also found that, when used as a prophylactic, EIDD-2801 can prevent severe lung injury in infected mice.
Colorized scanning electron micrograph of a VERO E6 cell (blue) heavily infected with SARS-COV-2 virus particles (orange), isolated from a patient sample. Image credit: NIAID.
EIDD-2801 is an orally available form of the antiviral compound EIDD-1931 (β-D-N4-hydroxycytidine). It can be taken as a pill and can be properly absorbed to travel to the lungs.
When given as a treatment 12 or 24 hours after infection has begun, EIDD-2801 can reduce the degree of lung damage and weight loss in mice. This window of opportunity is expected to be longer in humans, because the period between coronavirus disease onset and death is generally extended in humans compared to mice.
“This new drug not only has high potential for treating COVID-19 patients, but also appears effective for the treatment of other serious coronavirus infections,” said study senior author Professor Ralph Baric, a virologist at the University of North Carolina at Chapel Hill.
Compared with other potential COVID-19 treatments that must be administered intravenously, EIDD-2801 can be delivered by mouth as a pill.
In addition to ease of treatment, this offers a potential advantage for treating less-ill patients or for prophylaxis — for example, in a nursing home where many people have been exposed but are not yet sick.
“We are amazed at the ability of EIDD-1931 and EIDD-2801 to inhibit all tested coronaviruses and the potential for oral treatment of COVID-19,” said study co-author Dr. Andrea Pruijssers, an antiviral scientist at the Vanderbilt University Medical Center.
In 2019, the researchers reported that EIDD-1931 blocked the replication of a broad spectrum of coronaviruses.
They also performed the preclinical development of remdesivir, another antiviral drug currently in clinical trials of patients with COVID-19.
In the new study, they demonstrated that viruses that show resistance to remdesivir experience higher inhibition from EIDD-1931.
“Viruses that carry remdesivir resistance mutations are actually more susceptible to EIDD-1931 and vice versa, suggesting that the two drugs could be combined for greater efficacy and to prevent the emergence of resistance,” said study co-author Dr. George Painter, from Emory University and the Drug Innovation Ventures at Emory (DRIVE).
Clinical studies of EIDD-2801 in humans are expected to begin later this spring.
If they are successful, the drug could not only be used to limit the spread of SARS-CoV-2, but also could control future outbreaks of other emerging coronaviruses.
“With three novel human coronaviruses emerging in the past 20 years, it is likely that we will continue to see more,” said study first author Dr. Timothy Sheahan, from the University of North Carolina at Chapel Hill.
“EIDD-2801 holds promise to not only treat COVID-19 patients today, but to treat new coronaviruses that may emerge in the future.”
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Timothy P. Sheahan et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Science Translational Medicine, published online April 6, 2020; doi: 10.1126/scitranslmed.abb5883
