Md. Arafat Rahman :
Molnupiravir, an oral pill against corona virus received approval from the UK medicines regulator to be used against established infections of Covid-19. MHRA has issued a conditional marketing authorisation applicable in the United Kingdom, and an emergency use authorisation for Northern Ireland. Molnupiravir, sold under the brand name Lagevrio, is an antiviral medication that inhibits the replication of certain RNA viruses, and is used to treat Covid-19 in those infected by SARS-CoV-2.
Molnupiravir is a prodrug of the synthetic nucleoside derivative N4-hydroxy cytidine and exerts its antiviral action through introduction of copying errors during viral RNA replication. It 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 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, ß-D- N 4-Hydroxy cytidine 5′-triphosphate. During replication, the virus’s enzyme incorporates NHC-TP into newly made RNA instead of using real cytidine. Molnupiravir can swap between two forms, one of which mimics cytidine (C) and the other of which mimics uridine (U).
NHC-TP is not recognized as an error by the viruses 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. Molnupiravir can mimic both C and U. The wiggly lines stand for the connection to the pentose sugar and point in the direction of the minor groove.
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. ?
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.
The name of the drug was inspired by that of Thor’s hammer, Mjölnir. The idea is that the drug will strike down the virus, like a mighty blow from the god of thunder. 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 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. 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.
The drug reportedly worked equally well against different SARS-CoV-2 variants, including delta, gamma, and mu. One of Merck’s Phase 3 trial boards evaluating the drug’s efficacy recommended early discontinuation of the trial because it had met a predetermined endpoint, and because placebo administration might no longer be ethical in light of the drug’s substantial benefit to patients. An FDA monitoring board agreed.
Merck and Ridgeback submitted a 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 company announced plans to license the drug to generic manufacturers, to accelerate its availability. In addition to the United States, various other countries have reported interest in negotiating with Merck to procure stocks of molnupiravir pills, including the United Kingdom, South Korea, and Malaysia.
(Md. Arafat Rahman is Asst. Officer, Career & Professional Development Services Department,
Southeast University).
