June 01, 2020
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Scientists continue to develop potential treatments for and vaccines against COVID-19 at a breathtaking pace. Among the most recent reports, Timothy O. Sheahan and Ralph S. Baric at the University of North Carolina at Chapel Hill, George Painter at Emory University (Atlanta), and colleagues there and at Vanderbilt University (Nashville, TN) and the Centers for Disease Control and Prevention (Atlanta) found that an existing antiviral prodrug shows promise against the SARS-CoV-2 virus.

The authors’ work originated with a broad-spectrum antiviral compound called EIDD-1931 (β-d-N4-hydroxycytidine or uridine 4-oxime) that Painter and co-workers began to investigate in the early 2010s as a coronavirus treatment. (EIDD stands for the Emory Institute for Drug Development.) The molecule worked well against the SARS-CoV virus (which causes the severe acute and Middle East respiratory syndromes) in mice and dogs, but not monkeys.

Finding that the hydroxyl group in EIDD-1931 was being phosphorylated in monkeys’ stomachs and could not get to infected cells, the researchers sought a way to block phosphorylation. They esterified the hydroxyl group in EIDD-1931 with 2-methylpropanoic acid to produce the molecule EIDD-2801 [uridine 5′-(2-methylpropanoate), 4-oxime], which not only prevented phosphorylation, but also made the prospective prodrug more lipid-soluble and therefore more available orally. Enzymes in the bloodstream hydrolyze EIDD-2801 to liberate the active agent EIDD-1931.

Following on the success of EIDD-2801 against SARS-CoV, the researchers turned their attention to the novel coronavirus. In April, they were able to state that the administration of EIDD-2801 is “potently antiviral against SARS-CoV-2 . . . in primary human epithelial cell cultures without cytotoxicity.”

Things happened fast after that discovery. The scientists wrote the investigational new drug application for EIDD-2801 in 48 h; and the US Food and Drug Administration approved the application in a near-record 7 days. Drug Innovation Ventures at Emory (DRIVE), a spin-off from the university, then licensed EIDD-2801 to Ridgeback Biotherapeutics (Miami, FL) for human studies.

Painter believes that EIDD-2801 could work as a treatment for COVID-19 and other coronaviral diseases and, even better, as a prophylactic for individuals who have been exposed to a coronavirus.

EIDD-2801 hazard information*

Hazard class**Hazard statement
Acute toxicity, oral, category 4H302—Harmful if swallowedChemical Safety Warning
Skin corrosion/irritation , category 2H315—Causes skin irritationChemical Safety Warning
Serious eye damage/eye irritation, category 2AH319—Causes serious eye irritation Chemical Safety Warning
Specific target organ toxicity, single exposure, respiratory tract irritation, category 3H335—May cause respiratory irritationChemical Safety Warning

*This information is from CSNpharm (Arlington Heights, IL). Other vendors describe EIDD-2801 as not being a hazardous substance or mixture.
**Globally Harmonized System of Classification and Labeling of Chemicals. Explanation of pictograms.

EIDD-2801 fast facts

CAS Reg. No.2349386-89-4
Uridine, 4-oxime, 5′-(2-methylpropanoate)
Empirical formulaC13H19N3O7
Molar mass329.31
AppearanceWhite to off-white solid
Melting pointNot reported
Water solubility≈2 g/L

MOTW Update

Nitric oxide (NO) was the Molecule of the Week for February 4. 2013 . NO is a toxic gas; but in the body, it has an important role as a signaling molecule. Currently, it’s being evaluated as a treatment for COVID-19. During the 2003 SARS epidemic, Patients treated with NO recovered faster than patients who were not treated. At least 11 NO clinical trials are under way on COVID-19 patients.

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