|Other names||MK-4482, EIDD-2801|
|Chemical and physical data|
|Molar mass||329.309 g·mol−1|
|3D model (JSmol)|
Molnupiravir was originally developed to treat influenza at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE). It was then acquired by Miami-based company Ridgeback Biotherapeutics, which later partnered with Merck & Co. to develop the drug further. Molnupiravir was approved for medical use in the United Kingdom in November 2021.
Mechanism of action
Molnupiravir inhibits viral reproduction by promoting widespread mutations in the replication of viral RNA by RNA-directed RNA polymerase. It is metabolized into a ribonucleoside analog that resembles cytidine, β-D-N 4-Hydroxycytidine 5′-triphosphate (also called EIDD-1931 5′-triphosphate or NHC-TP). During replication, the virus's enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine.
Molnupiravir can swap between two forms (tautomers), one of which mimics cytidine (C) and the other of which mimics uridine (U). NHC-TP is not recognized as an error by the virus' proofreading exonuclease enzymes, which can replace mutated nucleotides with corrected versions. When the viral RNA polymerase attempts to copy RNA containing molnupiravir, it sometimes interprets it as C and sometimes as U. This causes more mutations in all downstream copies than the virus can survive, an effect called viral error catastrophe or lethal mutagenesis.
The first synthesis of molnupiravir was disclosed in a patent filed by Emory University in 2018.
In the first step, acetone is used as a protecting group to render two of the three hydroxy groups of uridine unreactive to treatment with the acid anhydride of isobutyric acid, which converts the third hydroxy group to its ester. Treatment with 1,2,4-triazole and phosphoryl chloride produces a reactive intermediate in which the triazole portion can be replaced with hydroxylamine. Finally, removal of the protecting group using formic acid converts the material to molnupiravir.: 93–95
Alternative patented routes to molnupiravir have been reviewed.
History of development
Molnupiravir was developed at Emory University by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE). In 2014, DRIVE began a screening project funded by the Defense Threat Reduction Agency to find an antiviral drug targeting Venezuelan equine encephalitis virus (VEEV), which led to the discovery of EIDD-1931. When turned into the prodrug EIDD-2801 (molnupiravir), the compound also showed activity against other RNA viruses including influenza, Ebola, chikungunya, and various coronaviruses.
Richard Plemper, a professor at Georgia State University, was the principal investigator of a grant from the National Institutes of Health to explore use of molnupiravir against influenza. In late 2019, the National Institute of Allergy and Infectious Diseases approved moving molnupiravir into Phase I clinical trials for influenza.
In March 2020, the research team pivoted to studying SARS-CoV-2, and successfully used the drug to treat human cells infected with the novel coronavirus. Plemper's group published in the journal Nature Microbiology the first demonstration that molnupiravir is orally active against SARS-CoV-2 in an animal model and established proof-of-concept that treatment completely suppresses virus transmission to untreated contacts within 24 hours.
Alleged safety concern
In May 2020, Rick Bright, director of the US Biomedical Advanced Research and Development Authority (BARDA), filed a whistleblower complaint, alleging that the Trump administration ignored his early warnings about the COVID-19 pandemic, pressured him to inappropriately fast-track unproven drugs, and illegally retaliated against him by removing him from his role as head of BARDA in April 2020.
Among these complaints, Bright objected to providing additional federal funding to Ridgeback Biotherapeutics to further develop molnupiravir into a treatment for COVID-19. He argued that although the drug had shown potential against coronaviruses including SARS-CoV-2, it had already received substantial government support.
COVID-19 clinical trial
In October 2021, preliminary results from a clinical trial (MOVe-OUT)[full citation needed] indicates that treatment with molnupiravir may reduce the risk of hospitalization and death from COVID-19.
Approval status and availability
In June 2021, the U.S. Department of Health and Human Services committed to buy US$1.2 billion worth of molnupiravir (approximately 1.7 million courses) from Merck if it received an emergency use authorization (EUA) or approval from the U.S. Food and Drug Administration (FDA).
In September 2021, Merck signed a voluntary licensing agreement with the Medicines Patent Pool (MPP) that allows MPP to sublicense molnupiravir and supply the COVID-19 oral medication to 105 low- and middle-income countries.
Merck submitted an EUA application to the FDA on 11 October, and the FDA's Antimicrobial Drugs Advisory Committee (AMDAC) will meet to discuss the EUA application on 30 November. Merck also plans to submit marketing applications to other global drug regulators. The Center for Drug Evaluation and Research (CDER) Antimicrobial Drugs Advisory committee of the U.S. Food and Drug Administration (FDA) is scheduled to meet on 30 November 2021, to discuss an emergency use authorization (EUA) application from Merck for emergency use of molnupiravir oral capsules for treatment of mild to moderate COVID-19 in adults who are at risk for progressing to severe COVID-19 and/or hospitalization.
In November 2021, molnupiravir was approved in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA) for the treatment of established infections of COVID-19. The MHRA issued a conditional marketing authorization applicable in the United Kingdom, and an emergency use authorization for Northern Ireland.
In October 2021, the Philippine Food and Drug Administration (FDA) has issued a compassionate special permit (CSP) to four hospitals in the Philippines in acquiring molnupiravir. This was further enhanced with the signing of a memorandum of agreement (MOA) between the Office of the Vice President of the Philippines and QualiMed Health Network, a local health care provider to prescribe the anti-viral drug through the Bayanihan E-Konsulta Program, a government-run telemedicine program.
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