As researchers rush to find treatments and cures for COVID-19, the first impulse is to turn to currently approved treatments where safety is already established. The primary focus has been on interventions that interfere with the lifecycle of the virus. Even as we work hard to understand the quality of evidence regarding all of these potential treatments, it may be helpful to review the various potential biological strategies.
Coronaviruses really have four basic phases in their lifecycle. They must first attach to and enter a host cell. Once inside, they express their replicase protein in preparation for the third phase which involves replication and transcription (making functioning copies) of its genome. Finally, in phase four, these “viral infants” interact with host cell structures to assemble and release new virions (mature viral particles). Current and planned clinical trials tend to focus on the first three phases.
Interference with the binding of COVID-19 to human host cells is an attractive target for researchers as there are a variety of approaches currently available. Losartan, designed as an anti-hypertensive, is postulated as a treatment for coronavirus because it binds to the same ACE receptors in the lungs as the virus. The hope is that it will effectively block viral attachment to lung cells. Similarly, APN01 is a manufactured mimic of those same receptors in the lung. It was developed for SARS and is thought to both block viral entry and reduce lung inflammation. Another promising approach is the use of monoclonal antibodies that bind the spike protein on the surface of COVID-19. If effective, it would prevent the virus from attaching to host cells. Finally, in this category, is a drug that has been used routinely in China and Russia to treat viral lung infections such as influenza, Arbidol. It is thought to bind to lipids and proteins in a way that prevents attachment of viruses to host lung cells. Arbidol is not being studied here in the U.S, though it is continuing to be used as “standard therapy” in China.
Preventing the virus from making its functional proteins is a second strategy under study. Similar to HIV and hepatitis C, coronaviruses have a string of RNA “beads” that are cut into pieces by M protease in order to manufacture critical proteins. The hope is that protease inhibitors designed for HIV (Nelfinavir) or Hep C (Tegobuvir) will be effective for COVID-19. Prulifloxacin, a broad spectrum antibiotic, that demonstrates protease inhibition in vitro, has also been put forward as a potential strategy to block the virus during this critical second phase of its lifecycle.
Another promising approach is to interfere with viral genome replication. Bictegravir employs this method to prevent HIV from multiplying. Remdesivir, initially developed by Gilead for SARS, is a chemically altered version of RNA nucleotides. A recent study suggests that this artificial nucleotide binds to the viral genome and then stops further replication.
Although not focused on the virus’ lifecycle, Chloroquine has received a lot of attention for its potential to lessen the severity of COVID-19 infections. Respiratory failure from coronavirus is thought to be at least partially caused by an overreaction of the body’s immune system (cytokine storm). Chloroquine and hydroxychloroquine have been used in the treatment of both malaria and inflammatory conditions, and at least part of their efficacy appears to be based on suppression of this cytokine induced immune response. Early reports offer some promise that they might lessen the severity of COVID-19 disease.
The most poorly understood potential therapy for COVID-19 is convalescent plasma infusion, a treatment dating back to the 1890s. This treatment appears to reduce viral load in serum and infected cells. Theories of its mechanism of action vary from blocking cell entry, binding and clearing of virions in the blood, and activation of the body’s natural immune response.
Obviously, there’s a lot of work ahead to test and refine treatments to manage the current pandemic, but it is reassuring to know that we can stand on the shoulders of all who have come before us and leverage their deep insights to guide us toward safe and effective solutions.
- https://www.biorxiv.org/content/10.1101/2020.01.28.922922v2.full
- https://www.jbc.org/content/early/2020/02/24/jbc.AC120.013056
- https://www.jstor.org/stable/4458734?seq=1
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369385/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627241/
- https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30141-9/fulltext
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