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April 27, 2021
Oral antiviral drug effective against COVID-19 in hamsters
At a Glance
- An oral antiviral drug called MK-4482 inhibited SARS-CoV-2 replication in hamsters.
- The drug might be able to prevent or treat COVID-19 outside of a clinical setting, and is currently being tested in people.
Only one antiviral drug, remdesivir, is currently approved for treating COVID-19. Remdesivir must be administered intravenously, which limits its use to clinical settings and hinders its use for preventing COVID-19 following exposure.
A team led by Dr. Heinz Feldmann from NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Dr. Michael Jarvis, a guest researcher at NIAID from the University of Plymouth, tested MK-4482, an experimental antiviral drug that can be taken orally, against COVID-19. The results of their study appeared on April 16, 2021 in Nature Communications.
Previous work by the researchers showed that Syrian hamsters were highly susceptible to SARS-CoV-2 infection. Infected hamsters had high virus levels in their lungs but developed only mild, transient clinical symptoms. Thus, Syrian hamsters provide a useful model for evaluating the efficacy of COVID-19 treatments.
The researchers used the hamster model to test MK-4482. Also called Molnupiravir, MK-4482 is a prodrug, meaning that it has no activity on its own. Rather, the body’s metabolism converts it into an active drug. The corresponding active form of MK-4482, called EIDD-1931, was developed in the early 2000s to treat hepatitis C virus. Recent studies in mice showed it to be effective against SARS-CoV-1 and MERS-CoV, viruses related to SARS-CoV-2.
The researchers first tested the ability of EIDD-1931 to stop SARS-CoV-2 replication in cultured human lung cells. Treatment with EIDD-1931 reduced viral replication by almost a thousand-fold. Notably, effective doses of the drug exhibited minimal toxicity to the cells.
Next, the researchers gave MK-4482 to two groups of hamsters. One group began taking the drug 12 hours before infection with SARS-CoV-2. The other began 12 hours after infection. Both groups continued taking MK-4482 every 12 hours until the fourth day after infection.
By the fourth day, hamsters in both treatment groups had about 10-fold less viral RNA in their lungs than untreated hamsters. Treated hamsters also had 100-fold fewer infectious viruses and fewer lesions in their lungs. However, the drug had no effect on the amount of virus shedding from the mouth. Hamsters in both treatment groups had similar levels of the active compound EIDD-1931 in their lungs.
MK-4482 is now in human clinical trials in SARS-CoV-2 infected patients. If it succeeds, MK-4482 could expand the available options for COVID-19 treatment. Because it can be taken orally, the drug could be used shortly before or after exposure to prevent COVID-19 symptoms. Combining MK-4482 with remdesivir may also be more effective than either drug on its own.
“In contrast to vaccines against SARS-CoV-2, we really don't have many drugs that are effective against the virus,” Jarvis says. “This is an exciting result that identifies MK-4482 as an additional antiviral against SARS-CoV-2. I think this additional control measure could prove to be really useful in the current pandemic.”
—by Brian Doctrow, Ph.D.
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References: Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model. Rosenke K, Hansen F, Schwarz B, Feldmann F, Haddock E, Rosenke R, Barbian K, Meade-White K, Okumura A, Leventhal S, Hawman DW, Ricotta E, Bosio CM, Martens C, Saturday G, Feldmann H, Jarvis MA. Nat Commun. 2021 Apr 16;12(1):2295. doi: 10.1038/s41467-021-22580-8. PMID: 33863887
Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection. Rosenke K, Meade-White K, Letko M, Clancy C, Hansen F, Liu Y, Okumura A, Tang-Huau TL, Li R, Saturday G, Feldmann F, Scott D, Wang Z, Munster V, Jarvis MA, Feldmann H. Emerg Microbes Infect. 2020 Dec;9(1):2673-2684. doi: 10.1080/22221751.2020.1858177. PMID: 33251966
Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID); The Vaccine Group, Ltd; University of Plymouth.