COVID-19 / Medicine / Drugs
Meet the Drugs Leading the Fight Against COVID-19
With the emergence of the COVID-19 outbreak came a rush of research activity to find treatments for the new pathogen. From the epicenter of the outbreak, Chinese researchers looked to their arsenal of existing antiviral drugs to find potential therapies. As the outbreak spread from Asia to Europe, so too did the investigation of these compounds as labs in Italy and France ramped up the investigation of potential drugs. As the outbreak hit the US, researchers at the University of Minnesota launched an ambitious clinical trial to test one of the drugs that showed potential efficacy against COVID-19. So what are these drugs and how do researchers expect them to fight a COVID-19 infection?
First let’s take a quick look at viral infections. Viruses are incredibly simplistic non-living organisms (there is some argument to this as viruses do show some of the accepted characteristics of life). Basically, viruses are a small segment of genetic material — either RNA or DNA — enclosed within a protein capsule called an envelope. The makeup of viruses beyond this is more complex, but viruses function in a common fashion. Unlike microbes like bacteria, viruses are not able to replicate on their own. For this reason, viruses rely on infecting more complex organisms like bacteria or multicellular organisms like humans. In doing so they highjack the host cells machinery to replicate their genome and envelope, forcing the host cell to churn out millions of new copies of the virus.
To accomplish this, viruses latch on to the outside of a host cell, poke a hole in the cell wall or membrane and inject their genetic material inside. Once inside a host cell, the machinery that reads the hosts genetic information also recognizes that from the virus and so replicates it.
Treating viral infections can be accomplished from a number of ways. Interfering with the viruses ability to latch on to a host cell is one way. Another approach is to clog up or alter the viruses genome is such a way that it is unable to be replicated. If you were to theoretically accomplish this, you could stop the replication cycle of a virus in its tracks.
Targeting the viral replication cycle is just one small piece of the overall puzzle of treating human viral infections. In hospital settings, drug therapies are also used to manage the human immune response to viral infections, which causes fever, rashes, cough and more serious symptoms like shortness of breath and sepsis. The immune response is quick and powerful, and is conducted by cells communicating with one another. If you have ever disturbed an ant hill by lightly poking one spot with a stick and seen the how the whole colony immediately springs into action, human immune cells do so in a similar fashion in response to pathogen infection. That response can often be so vigorous that the immune response is more dangerous than the infection itself.
And so, with that in mind we come to the drugs that are being investigated as possible treatments for COVID-19.
The Ebola outbreak in 2015 lead researchers in an similar scramble to find antiviral medications to treat that emerging outbreak. From this came the drug remdesivir, an antiviral that has show potency against a wide range of viruses. When COVID-19 emerged, researchers quickly turned their attention to this broad-acting antiviral drug.
COVID-19 is known as an RNA virus because the genome that it injects into host cells comes in the form of ribonucleic acid (RNA). Remdesivir is an analog to one of the building blocks that makes up RNA. If you imagine RNA as a string of pearls laced together, for this molecule to function properly the correct pearls need to be strung together, and they need to be uniform and recognizable by the host cell machinery. Remdesivir introduces a component to that string that forces a premature stop in the reading of viral RNA in the host cell (Warren T, 2016).
In an open letter to the editor at Cell Research, Wang et. al demonstrated research that showed that remdesivir effectively inhibits replication in the novel coronavirus causing COVID-19 (Wang M, et. al, 2020)
If you have ever heard of the use of quinine in tonic water to treat malaria, then you know the basic history of the development of the drug choloroquine and ultimately its close relative hydroxychloroquine. These drugs were developed as therapies against the mosquito-borne infection causing malaria.
While hydroxychloroquine use in malaria targets the affecting parasite, it has be shown to be effective in mitigating human viral infections. How this drug could be effective in treating COVID-19 is two part.
First, hydroxycholorquine has been show to interfere with the attachment phase of the virus. As viruses like COVID-19 attach to host cells, they are often gobbled up into internal bellies called lysosomes. These are the natural digesters within cells. Hydroxychloroquine causes an increase in pH within these lysosomes making it difficult for viruses to stay attached to the host cell wall and effectively blocking them from injecting their genetic material (Vincent M, 2005)
The second benefit of hydroxychloroquine comes in the treatment of the COVID-19 syndrome by helping to modulate the immune response to the viral infection and reducing the most harmful of symptoms. Chloroquine and hydroxychloroquine have been used in the treatment of inflammatory conditions such as arthritis, and autoimmune conditions such as lupus. Paradoxically, these compounds might help fight COVID-19 infections by ramping down the immune system in response to the virus.
Losartan is a drug used in the treatment of high blood pressure. It works by blocking the binding of a compound called angiotensin to its receptor. In the case of high blood pressure, angiotensin causes blood vessels to constrict, and ultimately helps the body retain water. These, when combined, elevate blood pressure. Losartan ultimately interferes with an enzyme called angiontensin-convering enzyme (ACE). It turns out that ACE is a site for COVID-19 binding in infection, and interfering with binding site may protect people from lung damage caused by COVID-19 infections (Gurwitz, 2020)
A recent clinical trail has begun at the University of Minnesota Medical School to investigate these compounds in COVID-19 infections. Researchers will investigate the role of these compounds as a prophylactic and in the treatment of COVID-19 post-exposure. More information on these trials can be found here: https://med.umn.edu/news-events/covid-19-clinical-trial-launches-university-minnesota
Gurwitz D, 2020: https://doi.org/10.1002/ddr.21656
Vincent M, et. al, 2005: https://doi.org/10.1186/1743-422X-2-69
Wang M, et. al, 2020: https://doi.org/10.1038/s41422-020-0282-0
Warren T, et. al, 2016: https://doi.org/10.1038/nature17180