Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, many drugs have been explored for repurposing against severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). While several have unfortunately led to a lack of results, plenty show promise. In a review published in Emerging Microbes & Infections, researchers from Sorbonne Université have been reviewing papers exploring different anti-COVID-19 drugs.
Study: A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality. Image Credit: iunewind
The review
The researchers reviewed papers examining COVID-19 between January 2020 and August 2021. They identified several virus-centered strategies, including using antivirals to prevent aggravation of clinical patients with mild symptoms or to limit the propagation of the virus.
Hydroxychloroquine and chloroquine were some of the first drugs scientists identified for these purposes. Unfortunately, hydroxychloroquine was later found to have no effect in severe cases of COVID-19 and did not affect mortality. Remdisivir showed significantly more promise, reducing recovery times by blocking inhibiting viral RNA-dependant RNA polymerase, preventing further replication of SARS-CoV-2. Lopinavir/Ritonavir inhibits the main SARS-CoV-2 protease but showed no clinical benefit, even with Favirpiravir. Ivermectin successfully limits SARS-CoV-2 nuclear import but again showed no clinical benefit.
A new antiviral compound, Molnupiravir, shows more promising results. Able to induce errors during viral replication, large clinical trials showed that it could reduce the rate of hospitalization by 50% as well as lowering mortality rates.
Another strategy revolves around supplementing the immune system with neutralizing antibodies or convalescent plasma (CP). Typically these target the SARS-CoV-2 spike protein. The S1 subunit of the spike protein contains a receptor-binding domain that binds to angiotensin-converting enzyme 2 (ACE2) to permit viral cell entry - disrupting the spike protein prevents the virus from entering the cell.
Normally, two antibodies are used in combination, and some of these combinations have been shown to lead to a faster decline of viral load, less severe symptoms, and less hospitalization. Injections of human ACE2 are currently being tested. The spike protein needs cleavage by a host protease - and bromhexine, an inhibitor of this protease - has been shown to reduce mortality in mild cases of COVID-19, although more testing is needed.
When COVID-19 progresses to the most severe symptoms, such as acute respiratory distress syndrome (ARDS), in which the lungs cannot provide enough oxygen to the organs, very few antiviral drugs can still have an effect. The researchers propose that more patient-centered strategies will likely show better results in these scenarios, such as administering broad-range anti-inflammatory drugs.
In many of the most severe cases, the immune dysfunction induced by SARS-CoV-2 can lead to neutralizing auto-antibodies against the body's own immune system, normally type I interferons (IFNs). Other immune-related symptoms can also be devastating in COVID-19 patients, such as cytokine storms, excessive inflammation, and over-expression of IL-6.
Treatment with Tocilizumab has shown increased survival and recovery rates for severe COVID-19 patients. Anti-IL-6R antibodies result in lower mortality rates in COVID-19 patients, but only if the levels of CRP are above 15mg/mL. Anankinra reduces the expression of both IL-6 and CRP and can promote survival by blocking interleukin receptors. Infusion of mesenchymal stem cells (MSCs) display anti-inflammatory properties, and infusion of ACE2 negative MSCs has shown a reduction in mortality. Patients also displayed reduced TNF-alpha and plasma CRP levels, but more research is required.
Dexamethasone shows broad anti-inflammatory action and reduces CRP levels. It has been shown to limit mortality rates and the need for mechanical ventilation. Still, it is detrimental in the early stages of the disease and in those not suffering from severe disease. It has been approved against severe COVID-19. This is because the inflammation response is helpful in the early stages of the disease, but by the later stages, the same response is much more damaging for the lungs.
The Renin-Angiotensin-System (RAS) may be over-activated in older SARS-CoV-2 patients, leading to increased production of Angiotensin-II, which promotes inflammation and senescence, leading to the increased susceptibility seen in the elderly. While there is little current information on the drugs that could restore the balance of the RAS, the researchers propose that injections of soluble hACE2, AT2R activators (68), AT1R blockers (ARBs) (65), or ACE inhibitors (ACEI) could have beneficial effects.
Conclusion
The researchers highlight the importance of their review in revealing the importance of focusing on patient-centered strategies for patients suffering from more severe COVID-19, as antiviral drugs appear to lose their effectiveness in the illest patients. This review could help inform healthcare providers and drug developers, ensuring the right care is delivered to the right patients.
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