Molnupiravir: A Pill to Treat COVID-19

By Prof. Kirthi Tennakone (ktenna@yahoo.co.uk )

A week ago, pharmaceutical companies, Merck and Ridgeback Biotherapeutics, announced an orally admissible pill that cuts-down COVID-19 hospitalisation deaths by about 50 percent. To imply its power, the drug has been named molnupiravir. According to Germanic mythology, a blow of lightning and thunder emanate when the God Thor strikes his hammer like combat weapon, Mjolnir.

The world is witnessing the strength of vaccines in taming the pandemic. The other weapon absolutely essential to ease the calamity and alleviate the suffering is indisputably a curative medicine – preferably a drug, in pill form, to be taken by mouth.

Antibacterial and Antiviral Drugs

One of the most important conjectures humans continue to maintain is illnesses can be cured by intervention. Henceforth, an untiring effort is diverted to find remedies for every disease and complication. The successes of this endeavor are too numerous to exemplify – to name a few; now we have cures for dreadful diseases such as tuberculosis, leprosy and meningitis.

With the advent of the germ theory of Louis Pasteur, physicians concluded infectious diseases can be relieved if ways are found to kill causative microorganisms in the human body. Pasteur’s work led to the development of disinfection – ways of destroying pathogens harboured outside the human body. Obviously, these techniques are too harsh to destroy germs in the human body.

One hundred years ago, German chemist and physician, Paul Ehrlich, argued that substances attacking bacteria while saving human cells should exist. He said, bacteria absorb certain colourful dyes, leaving human cells intact. Thus dyes and other chemical compounds which selectively interact with bacteria could serve as potent medicines to combat infectious diseases. Inspired by the foresight of a genius; doctors, searched chemical compounds efficacious in curing infections, but innocuous to the human body. In 1935, German physician Gerhard Domagk injected the reddish coloured dye, named prontosil, to his daughter, dying of streptococcal septicemia, and cured her! This was the birth of the sulfonamide – the first broad spectrum antimicrobial. Domagk was awarded the 1939 Nobel Prize for Physiology, citing; he made the dream of Paul Ehrlich a reality and the discovery means nothing less than a revolution in medicine.

The first antibiotic (chemical compound produced one kind of microbes to inhibit the growth of another); penicillin was discovered by Alexander Fleming 1928. Its clinical use, which began in the early 1940s, opened the era of antibiotics and related synthetics. Antibiotics were found to treat almost every bacterial infection, adding 20 odd years to global life expectancy!

Several hundred virus species cause identified diseases in humans – some preventable by vaccination or self-limiting owing to acquisition of natural immunity and a handful responding to curative treatments. Mortality and morbidity of viral disease greatly constrain the healthcare systems all over the world, because a large percentage of the population regularly catch these infections and ready treatments are generally unavailable.

Unlike bacteria, viruses replicate inside host cells intermingling their genetic essence with that of the host. For this reason, it is extremely hard to find agents capable of eliminating the virus without injuring the host cells.

The first antiviral drug Idoxuridine, originated around the late 1950s as a spin-off of cancer research and later found to be a satisfactory cure for herpesvirus infection in eyes and skin. Because of its high toxicity, the drug was prescribed only for topical application. After experience with Idoxuridine; pharmaceutical chemists were of the opinion safe injectable or oral antiviral agents would be an exceptionality. The situation changed when two biochemists Gertrude Elion and George Hitching, initiated a targeted drug design instead of trial and error experimentation. Their work paved the way for synthesis of the potent antiviral drug acyclovir – a safe antiviral used for treatment of herpes, singles and chicken pox. Both received the Physiology Nobel Prize 1988 for work done during the decade, beginning 1945.

Modern targeted antiviral drug design adopt number of different strategies to inhibit viral invasion of human tissue. Mainly; blocking binding of viruses to receptors in cells of the host, arresting escape of the virus genetic material from its outer envelope or introducing agents to derange the replication process.

Most antivirals, currently used and proven to be effective, belong to the third category and referred to as nucleoside analogues. Nucleosides are biochemical molecules, very similar to nucleotides in DNA and or RNA involved in writing of the genetic code. They play an integral role in encoding, transmitting and expressing genetic information. Nucleoside analogue means a molecule tailored slightly different from the naturally occurring counterpart. When the virus mistakenly utilises the analogue which mimic the natural one; the replication process is derailed, stopping proliferation of the virus.

Antivirals widely prescribed to treat influenza, HIV, viral hepatitis, herpes are nucleoside analogous. Remdesvir an approved injectable drug for COVID-19 and the oral molnupiravir, disclosed by Merck, also fall into the same class of antiviral medications.

Molnupiravir: Promising oral COVID-19 drug

Molnupiravir was developed by Drug Innovation Ventures at the Emory University, United States, and patented in 2018, is now classified as an investigational drug for treatment of COVID-19. Originally intended to be tested for treatment of influenza and later shown to be effective in inhibiting SARS-CoV-2 in human respiratory tract epithelial cell cultures and coronaviruses in mice. According to Merck Pharmaceutical Company, in an international clinical trial, molnupiravir, reduced the risk of hospitalisation and death by nearly 50 percent among higher risk people diagnosed with mild to moderate illness.

Mechanism of action: the error catastrophe

Molnupiravir is a prodrug – meaning the active ingredient produced after its metabolism inside the body. Prodrug approach has the advantage in stabilising the active component and lessoning the toxic side effects. Prodrug form allows oral administration. After absorption in intestines and entry into body tissue; molnupiravir is converted into the active component hydroxycytidine which is a nucleoside analogue. This analog mimics two natural nucosides utilised by the virus for its replication. This confusion leads to a progeny of heavily mutated variants of which majority deleterious. The result is the eventual extinction of the virus. Evolutionary biologists refer to this phenomenon as ‘the error catastrophe’.

When a species mutates fast making errors, the species goes extinct when the mutation rate exceeds a threshold.

Judging from the veracity investigations, conducted, and scientific soundness of arguments presented, molnupiravir seems to be something the world is eagerly awaited. Yet rigid science may not grant approval for its wide clinical use without further scrutiny to confirm its efficacy and side effects. Contrastingly, in Sri Lanka some have promoted quackeries with no rational basis whatsoever as cures for COVID-19. Fools rush where angels fear!