A Closer Look at the COVID-19 Therapeutic Landscape
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When SARS-CoV-2 became a global pandemic in early 2020, not much was known about the new coronavirus, and there were no vaccines or drugs to treat ill patients in hospital. While the virus is still prevalent in society and case numbers remain high, great progress in scientific research and healthcare has been made over the past 18 months.
The vaccines were the major breakthrough, firstly, to save lives and to reduce the strain placed on hospitals and other healthcare facilities. The vaccines also brought society one step closer to the “normality” that we once knew. However, despite their high efficacies, it is unclear how long the vaccines offer protection against the virus and booster shots are now being administered.
Alongside vaccine research and production, pharmaceutical companies have been working tirelessly to find drugs to effectively and safely treat COVID-19 related symptoms. As of late early November 2021, two oral antiviral drugs have emerged, generating a lot of enthusiasm: molnupiravir and paxlovid (PF-07321332), from pharmaceutical giants Merck and Pfizer respectively. Both drugs have been shown to cause a remarkable reduction in COVID-19 symptoms in global clinical trials. Let’s explore the back story of where these drugs came from, how they work and the clinical trial data that is available.
Merck carried out a global Phase III clinical trial that required participants to have an underlying medical condition – such as heart disease, obesity or diabetes – or they had to be over 60 years old, making them extremely vulnerable to severe COVID-19-related illness. Upon analysis of its interim results, Merck concluded that molnupiravir reduces the risk of hospitalization by 50% and suggested that it also reduced viral transmission. The company did not report any serious side effects associated with the drug, and are not concerned about the possibility of mutagenic side effects, which had been an initial consideration due to the drugs mechanism of action. Molnupiravir was also found to work equally well against the different SARS-CoV-2 variants and there is little chance of the virus developing resistance, again, due to the mechanism of action. These results were drawn from an initial sample size of 775 people. As the results were so impressive, full enrolment for the trial was deemed unnecessary.
Molnupiravir was approved for use in the UK, marketed as Lageviro, on November 4. It is the first oral antiviral prescribed for treating COVID-19 symptoms. The oral route of administration is hugely advantageous, as previously approved antivirals – such as remdesivir – are either administered intravenously or intramuscularly, which puts more strain on hospitals and makes it difficult for sick people to get the drugs quickly enough. It is recommended that patients get the drug within five days of symptom onset, otherwise its effectiveness is likely to diminish if symptoms become more severe.
Molnupiravir was derived from a drug that had been known for many years, going back as far as the 1970s. In 2014, the drug innovation company, DRIVE, based at Emory University in Atlanta, Georgia began looking at molnupiravir’s predecessor as a possible treatment for Venezuelan equine encephalitis virus. After a small modification, they designed molnupiravir and found that it was effective against Ebola, chikungunya and influenza. In 2015, Venderbilt University in Nashville, Tennessee and the University of North Carolina became involved and started testing it against different coronaviruses. Researchers found that the drug was highly effective against different coronaviruses, including MERS-CoV and SARS-CoV and started to test molnupiravir against flu viruses. Then the pandemic struck, and with it, their attention turned to SARS-CoV-2. The initial results were very encouraging and in 2020, molnupiravir was licensed to Ridgeback Therapeutics in Miami, who alongside Merck, began human trials.
How does it work?
SARS-CoV-2 is a single stranded RNA virus and, like all viruses, to survive, it has to replicate by making new copies of its RNA before producing new viral proteins. This process relies upon the RNA-directed RNA polymerase (RdRp) enzyme. RdRp helps to join together the correct nucleoside molecules in a long chain; specifically, guanosine with cytidine and adenosine with uridine. If the function of RdRp can be interfered with, the process comes to a grinding halt.
Molnupiravir is a prodrug, meaning it is not administered in its active form, but is converted to the active form once inside the body, where it mimics both cytidine and uridine. It changes its structure through a process called tautomerism. Crucially, the virus can’t tell the difference between the drug and the actual cytidine and uridine nucleosides, meaning it sporadically incorporates molnupiravir into its RNA template sequence. When the virus then tries to replicate and copy the RNA template strand, a huge number of "mistakes" or mutations are made and its genetic code becomes a long way from what it is supposed to be. When this occurs on a large enough scale, the virus cannot survive. It’s a process known as “lethal mutagenesis” or “catastrophic mutation”. Molnupiravir is therefore classed as a mutagenizing agent.
There are two problems usually associated with drugs and viruses. Firstly, viruses have a mechanism to check if there are any mistakes made during the replication process, which it can fix, allowing it to replicate correctly. Crucially, molnupiravir is not detected by this mechanism. Secondly, viruses often become resistant to drugs via mutations. Because of the random nature of how molnupiravir is incorporated into the RNA, it is very difficult for the virus to mutate and become resistant. Side effects should be minimal as RdRp is not present in healthy cells, making the drug highly specific. There is also a lot of optimism that molnupiravir could be used against other viruses as the enzymes are almost identical across different viruses.
Paxlovid is based on a previous Pfizer antiviral drug called Lufotrelvir, which had to be administered intravenously. Due to the aforementioned advantages of oral administration, Pfizer’s research focused upon modifying lufotrelvir for oral administration, the end result being paxlovid.
How does it work?
Paxlovid works differently to molnupiravir, as it is a protease enzyme inhibitor. Via a process known as proteolysis, protease enzymes cleave large polyproteins to produce smaller proteins that are essential for viral replication. If the protease enzyme can be inhibited, this important cleavage step cannot occur and the replication is stopped; therefore, these enzymes make excellent drug targets. Paxlovid is a tripeptide mimetic drug (it mimics the natural substrate) that specifically targets the SARS-CoV-2-3CL protease enzyme, sometimes referred to as the “main protease”. The drug forms a covalent bond to a cysteine residue in the catalytic domain of the enzyme, rendering it ineffective; the cysteine residue is responsible for cleaving the polyproteins. SARS-CoV-2-3CL is an ideal drug target, as it is not present in healthy cells and therefore side effects should be minimal.
Paxlovid is combined with a low dose of another antiviral, ritonavir, to prolong its activity. Ritonavir was initially used as an HIV antiviral drug but is now only used in combination therapies. It inhibits the cytochrome P450-3A4 enzyme that is known to metabolise protease inhibitors. By inhibiting the metabolism, paxlovid remains in its active form longer, therefore increasing its efficacy.
From the results, it is easy to see why these two drugs are causing great optimism in the fight against SARS-CoV-2. There are also more antivirals in the pipeline from other pharmaceutical companies – something to look out for in the coming months.