Since its advent in 2019, the SARS-Covid virus has been creating ripples as the most serious virus infection till date. The virus has caused millions of death worldwide and a resultant pandemic situation lasting till date. Originated from a species of bat, the virus, in due course, spread to humans. Through air borne and surface contamination, it has steadily continued the transmission process.
Because of its complex molecular structure and that of its variants, the damage took researchers and health experts time to rectify. Treatment options either did not pass the safety standards or were unreliable. That’s why approval of Molnupiravir to treat Covid in UK is no less than a breakthrough achievement.
A word about Molnupiravir
Molnupiravir was developed years before the pandemic but for other reasons. Molnupiravir development can be traced as far as to 2003 when it was developed as a treatment against influenza and flu symptoms. Animal testing of Molnupiravir by then showed its effectiveness against a range of RNA viruses mainly Hepatitis-C with seasonal and pandemic flu viruses as well. Because of absorption issues and possibility of inducing mutations in host cells, it was abandoned soon after. It was the induced mutation quality that was regulated for Covid use.
Molnupiravir was subsequently converted for modification purposes and developed into a prodrug for treatment of Encephalitis in 2013 before its reuse in 2021.
Before understanding about a prodrug, it is important to understand about bioavailability of a drug.
Bioavailability of Molnupiravir
Bioavailability of a drug is the absorption capacity or the fraction of administered drug that reaches systemic circulation. Usually factors like the absorption capacity of the body and proper utilization of drug determine the drug’s bioavailability. At times, as in case of Molnupiravir, it is the physical and formulation properties of the drug that result in bioavailability issues. To rectify this issue and allow its safe use, Molnupiravir was modified into a prodrug.
What is a Prodrug?
In medical terms, a prodrug is a medication or compound that after administration is converted by the body or metabolized into a pharmacologically active drug. This is important when the bioavailability of a drug is questionable. A prodrug improves the selective interaction of a drug with the cells and tissues of gastrointestinal system. This allows easy absorption, faster breakdown of the drug in the system and subsequently its safe metabolism and excretion. A prodrug is said to be:
- Type I when it is bioactivated intracellularly
- Type II when it is bioactivated extracellularly
Molnupiravir is a type II prodrug of synthetic nucleoside derivative N⁴- hydroxycytidine. This anti-viral medicine has been approved by the UK government as a treatment option for mild to moderate symptoms of Covid-19 in non-hospitalized patients.
A basic understanding for Structure of Covid virus
For better understanding of Molnupiravir action it is important to know about RdRp. RNA dependent RNA polymerase, also known as RdRp, is an enzyme that catalyzes the replication of RNA from a RNA template. RdRp is not present in human beings as they do not need to amplify their RNA. But RdRp is crucial for viruses, as it forms the basis of their replication mechanism.
Research into the structure of the Covid virus has shown that the virus, after entering into the human cell, reaches to the host cell nucleus and hijacks its machinery. Using this RdRp enzyme, it starts replicating its RNA genome into them. This is repeated on an extensive basis as the replication mechanism of virus.
Let’s talk about the Covid virus in detail!
The SARS-COV-2 is essentially a Betacoronavirus like SARS and MERS. Till date 7 strains of human corona virus have been detected out of which SARS- Covid 2 and its variants form only a part. Identified as positive sense RNA virus, the spike protein and RdRp enzymes play an important role in the function of virus.
While the spike proteins of the virus enable its attachment to the ACE-2 receptors, Rdrp enzyme enable the virus to multiply at a 100 fold rate. The ACE-2 receptors are human enzymes found in the lining of important areas like nasal cavity, lungs, gastrointestinal system and connective tissues. The presence of ACE-2 receptors makes these areas target spots of viral entry and subsequently susceptible to great damage.
The replication of the virus initiates an aggressive inflammatory response from the host cell known as a cytokine storm. The aftermath of a cytokine storm is mainly destruction of human tissues in the form of capillary damage, blood barrier damage, and diffuse alveolar damage. These culminate to multiple organ failure followed by death of the individual.
Mechanism of action of Molnupiravir
After ingestion of Molnupiravir in a human body containing the active form of the virus, NHC, the active component of the drug circulates systematically and is converted into NHC triphosphate. In due course the Covid virus starts its work on the cell nucleus. Because of Molnupiravir, the RdRp enzyme of the virus uses the active form of the medication as a substrate instead of the regular cell substrate. The incorporation of NHC triphosphate of Molnupiravir instead of the human substrates of cytidine or uridine lead to faulty replication of the virus. The result being mutations of virus that are non-infectious or unable to further replicate.
In order to test the efficacy of Molnupiravir, an international trial was conducted on 1433 adult patients who had tested Covid positive. The trial was double blind, placebo controlled in phase-3 of its trial period. Unvaccinated patients with mild or moderate Covid-19 who had symptoms for 5 days and we’re at a risk for disease progression were selected. They were administered four 200mg of capsule twice daily for 5 days. The end point was targeted to be either hospitalization of them or their death within 29 days.
At a planned interim analysis of 775 patients, Molnupiravir proved superior to placebo in terms of preventing hospitalization or death. Adverse effects were reported in 30.4% of the Molnupiravir group and 33.0% in the placebo group. The results showed that early treatment of Molnupiravir in unvaccinated adults could reduce the risk of hospitalization or death to a considerable extent.
What makes Molnupiravir better than other antiviral?
Antivirals or medications against the Covid virus are usually termed or included as medications that prevent active spreading of the virus along with taking care of viral replication. The work of antivirals is to inhibit viral entry through ACE-2 receptors and transmembrane proteases. Also antiviral has the greatest impact in the early stages of viral replication to prevent the hyper inflammatory reactions at later stages of infections. All of which is achieved through Molnupiravir.
Nineteen months into the pandemic, Molnupiravir is the first oral anti-viral drugs approved for active treatment of Covid positive patients. It is affordable and scalable because of which it can be widely distributed in lower-income countries. The oral quality of the drug makes it easier for manufacturers to bulk manufacture and store it. The same quality reduces hospital costs and in-treatment costs for patients by enabling them to take it at home unlike Remdesivir that can only be administered by injections.
The catch in FDA approval
Molnupiravir is FDA approved but with certain guidelines attached to its medical uses. It is restricted to situations where other FDA-approved treatments see either inaccessible or aren’t clinically appropriate. It is then that Molnupiravir comes forward as a useful treatment protocol for Covid-19 patients at high risk of hospitalization or death.
In a nutshell, Molnupiravir can be used in patients getting home treatment. Those declared clinically unsuitable for the use of subcutaneous injections or with hypersensitivity reactions to Remdesivir can take Molnupiravir on physician’s prescription. Because of the immense pressure on the manufacture and distribution of Remdesivir, it can used in cases of Remdesivir non-availability as well. Most importantly in cases of insufficient hospital arrangements or shortage of hospital facilities, it can help the patients being treated at home.
But there are hiccups here as well!
Despite the immense prognosis that Molnupiravir holds and its selective FDA status, it cannot be used in everyone or in any conditions.
Animal reproduction studies have shown fetal harm with the use of Molnupiravir. This makes it unsuitable for use in pregnant or breastfeeding women. Molnupiravir is not authorized for use in patients below 18 year as it may affect their bone and cartilage growth. Additionally it is not authorized for pre-exposure or post-exposure prevention of Covid-19 or in patients hospitalized due to the effects of Covid-19 virus. The benefit of Molnupiravir is best observed before hospitalization of the affected patients.
At the end of the day
We have come a long way from using medications not deemed safe for Covid use to actually getting a FDA approved tablet for Covid. Its oral mechanism of intake makes it convenient for the common man to access and use it safely without needing to go to hospital for its use. Additionally it is cost effective and thus has the potential to be of global use. But it is in its initial stages of distribution that restrict its supply and overall availability. The production of Molnupiravir needs to be on a large scale basis for better availability. Public awareness needs to be spread regarding the pros with potential dangers and risks associated with the medication. More research needs to be conducted on Molnupiravir in depth about its prodrug properties.