I continue to be amazed by science. The ability to predict to the second when an eclipse will occur at a specific location in the world, the know-how to build a jetliner that requires the cohesive working of over four million parts and the production of computers with all their marvellous functions are astounding examples of human ingenuity. To say nothing about reaching into your pocket for the smartphone that in a fraction of a second will provide an answer to almost any question you may have. Mind-boggling. But perhaps even more amazing is the intricately detailed knowledge we now have of the workings of the human body and of the wrenches that can be thrown into its works. This is readily apparent when one starts to delve into the efforts of researchers who try to extricate us from the clutches of COVID-19 by getting down to molecular biology.
The Holy Grail here is the prevention of the replication of the SARS-CoV-2 virus once it enters the body. Vaccines do this by generating specific proteins called antibodies that recognize a virus and can inactivate it by various mechanisms before it can cause an infection. But what can be done once a virus has successfully entered a cell and has hijacked its reproductive machinery to replicate itself? If this isn鈥檛 stopped, the host cell will begin to spew out viruses that then create havoc around the body. Time to open the door to antiviral drugs!
Replication of the Sars-CoV-2 virus involves copying the virus鈥� genetic code, namely the instructions to produce all the necessary parts that make up the virus. Just like an airplane or a skyscraper cannot be built without a blueprint, a virus cannot be built without a blueprint. In the case of the coronavirus that we have been struggling with, that blueprint is a molecule of ribonucleic acid, commonly termed 鈥淩NA.鈥� Replication of a virus can be prevented if the molecular structure of its RNA is disturbed in such a way as to prevent it from generating the molecules the virus needs to force a host cell to carry out its wishes. An analogy would be spilling ink on a critical part of a blueprint making it impossible to read the instructions.
There are several ways 鈥渋nk can be spilled on a virus鈥� to produce an antiviral drug. Remdesivir, the first antiviral approved for Sars-CoV-2 infection, was initially developed for the treatment of Ebola. The drug mimics adenosine, one of the building blocks of RNA, and can thus get incorporated into a virus鈥� RNA. This gums up the virus鈥� works by preventing the altered RNA from sending out the proper instructions for the synthesis of RNA polymerase, the enzyme that a new virus needs to start putting together its own RNA. Without a properly functioning RNA polymerase, the developing RNA chains come up short and become dysfunctional. The newly developing virus withers away. But there is a problem with remdesivir in that it has to be given intravenously once symptoms have presented, usually in a hospital setting. An oral antiviral drug that does not require hospitalization is obviously preferable.
Molnupiravir, Merck鈥檚 new drug, (prospective name Lagevrio) has a similar mode of action in that it also mimics building blocks of RNA, this time cytidine and uridine. Unlike remdesivir, this doesn鈥檛 stop new RNA from being formed, but the new versions are 鈥渕utants鈥� because the incorporation of cytidine or uridine changes the shape of the RNA molecule. In our blueprint analogy, it would mean erasing part of an airplane鈥檚 blueprint and replacing it with a segment taken from that of a skyscraper. The more of these erasures, the greater than chance the plane will not fly. Similarly, when enough mutations occur in a virus鈥� RNA, it cannot send out the proper instructions for multiplication. In a trial, when molnupiravir was given at the onset of symptoms, it reduced hospitalization and death by half. Merck emphasizes that there is no evidence that the drug will alter human DNA, a legitimate concern based on molnupiravir鈥檚 mode of action.
Pfizer also has a novel antiviral in the works. Paxlovid is a 鈥減rotease inhibitor,鈥� which as the name suggests, inactivates an enzyme known as a protease. Enzymes are biological catalysts and proteases specifically speed up the breakdown of proteins. In our bodies, proteins are constantly being synthesized from amino acids in food and are also being constantly broken down into the component amino acids and into smaller chains of amino acids called peptides. These amino acids and peptides can then be used to make novel proteins including ones that make up our muscles, our hair and our nails as well as the enzymes that control many bodily functions. Similarly, viruses also synthesize large proteins called 鈥減olyproteins,鈥� based on instructions from its RNA. These are then broken down by proteases into smaller proteins that the virus needs to invade a cell and replicate. Oral Paxlovid interferes with this breakdown process. In a preliminary trial, a combination of Paxlovid with ritonavir, a drug that interferes with the activity of an enzyme that would normally degrade Paxlovid, cut the risk of hospitalization by around 85%, even in the face of the highly transmissible Delta variant.
Both Paxlovid and Lagevrio are set to have an impact on the treatment of COVID-19 infections. These of course are not substitutes for the vaccines that can prevent infections but do offer a possible treatment to reduce the severity of an infection. There is a concern, however, that the introduction of these drugs may slow vaccination rates should vaccine-hesitant individuals start thinking that infection is no big deal because it can be dealt with by a pill. As the saying goes, an ounce of prevention is worth a pound of cure. And here鈥檚 hoping that a small scent of true science can mask the stench produced by the growing piles of pseudoscientific rubbish.
