Treatment with MK-4482 could potentially mitigate high-risk exposure to SARS-CoV-2


An experimental antiviral drug can significantly decrease levels of the virus causing COVID-19 and the damage it causes in the lungs, according to new research.

Scientists from the United States National Institutes of Health (NIH) and the University of Plymouth found that MK-4482—initially developed to treat influenza – was effective when provided up to 12 hours before or 12 hours after infection with SARS-CoV-2.

Writing in Nature Communications, the researchers say it suggests treatment with MK-4482 could potentially mitigate high-risk exposure to SARS-CoV-2 and might be used to treat established SARS-CoV-2 infection alone or in combination with other agents.

The drug is currently undergoing human clinical trials, but researchers say its ability to be provided orally could offer a significant advance on existing antivirals being used to treat COVID-19.

Remdesivir, for example, has already been approved by the United States Food and Drug Administration but must be provided intravenously, making its use primarily limited to clinical settings at later stages of disease.

The research was conducted at Rocky Mountain Laboratories, part of NIH’s National Institute of Allergy and Infectious Diseases in Hamilton, Montana.

Dr. Michael Jarvis, Associate Professor of Virology and Immunology at the University of Plymouth and a guest researcher at NIH, was a senior author on the study.

He has expertise in developing vaccines designed to prevent infections jumping from animals to humans, and has also been working to adapt novel vaccine platform technology to prevent future human coronavirus zoonotic emergence.

Speaking about the current study, Dr. Jarvis said:

In contrast to vaccines against SARS-CoV-2, we really don’t have many drugs that are effective against the virus.

This is an exciting result that identifies MK-4482 as an additional antiviral against SARS-CoV-2. The drug, also called Molnupiravir, is in the final stages of human clinical trials in SARS-CoV-2 infected patients.

“If the final human data show a similar antiviral effect, our preclinical animal data suggests it may be suitable for use as an orally administered pill following exposure to the virus, similar to the way we use Tamiflu for influenza. I think this additional control measure could prove to be really useful in the current pandemic.”

The same research group from Rocky Mountain Laboratories developed a model last year which uses hamsters to mimic SARS-CoV-2 infection and mild disease in people.

The current research involved three groups of hamsters—a pre-infection treatment group, a post-infection treatment group and an untreated control group—and for the two treatment groups, scientists administered MK-4482 orally every 12 hours for three days.

At the conclusion of the study, the animals in each of the treatment groups had 100 times less infectious virus in their lungs than the control group. Animals in the two treatment groups also had significantly fewer lesions in the lungs than the control group.

COVID-19 is primarily a respiratory disease, but many extrapulmonary effects and complications have been described. Cough and fever are the most frequent symptoms, followed by myalgia, headache, dyspnea, sore throat, diarrhea, nausea/vomiting, and anosmia or ageusia (5).

These initial COVID-19 symptoms are not easily distinguished from other respiratory infections such as influenza; therefore, a broad-spectrum treatment would be advantageous for empiric therapy. Complications of COVID-19 include respiratory failure, cardiovascular events, thromboembolic events, and inflammatory damage (6), and respiratory sequelae are anticipated in patients with severe disease (7).

Thus, administration of a potent, direct-acting antiviral at various stages of viral replication may reduce not only acute disease symptoms and transmission, but also complications and sequelae of untreated progressive disease.

Molnupiravir (also known as EIDD-2801/MK-4482) is a prodrug of the ribonucleoside analog ß -d-N4-hydroxycytidine (EIDD-1931 [NHC]), which is phosphorylated intracellularly to the active 5′-triphosphate. Molnupiravir has demonstrated the potential to treat infections caused by several RNA viruses, including pandemic-capable coronaviruses and influenza viruses, and encephalitic alpha viruses such as Venezuelan, Eastern, and Western equine encephalitis viruses in nonclinical models.

The primary mechanism of action of molnupiravir against RNA viruses is viral error catastrophe (8, 9), a concept that is predicated on increasing the viral mutation rate beyond a biologically tolerable threshold, resulting in impairment of viral fitness and leading to viral extinction.

Molnupiravir has demonstrated in vitro activity against SARS-CoV-2 in human airway epithelial cell cultures.

Prophylactic and therapeutic administration of molnupiravir to mice infected with SARS-CoV or MERS-CoV improved pulmonary function, and reduced virus titer and body weight loss (10). In the ferret influenza model, treatment of pandemic influenza A virus with molnupiravir resulted in reduced viral shedding and inflammatory cellular infiltrates in nasal lavages, with a normal humoral antiviral response (11).

Here we report the results of a first-in-human, phase 1, randomized, double-blind, placebo-controlled study to determine the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of molnupiravir in healthy subjects. A randomized, open-label, crossover evaluation in the fed (high fat) and fasted states was also conducted to assess the effect of food on the pharmacokinetics of single doses of molnupiravir.

reference link:

More information: Kyle Rosenke et al. Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model, Nature Communications (2021). DOI: 10.1038/s41467-021-22580-8


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