How is the search for a therapy against SARS-CoV-2 proceeding?

In this article I update you about the most recent findings in the research of a valid therapy against SARS-CoV-2, the virus responsible for the Covid-19 pandemic.

The biggest surprise comes from a drug approved against arthritis rheumatoid and other immune diseases, which had positive effect on Covid-19 patients in China and Italy. Immune diseases are caused by uncontrolled activation of the immune system, which attacks and destroys the organism itself. This drug, called tocilizumab (sold as Actemra), targets the receptor of interleukin-6 (IL-6). IL-6 is a molecule of the immune system that plays important pro-inflammatory functions when it binds to its receptor. Actemra competes with IL-6 in the binding to the receptor, therefore reducing the level of the inflammatory response. Covid-19 patients have an ongoing immune response, and sometimes this leads to the so-called “cytokine storm”: a dangerous phenomenon characterized by overproduction of immune cells and molecules. This immune overreaction leads to lung inflammation, worsening patients’ condition. Actemra seems to help relieving inflammation within 24-48 hours on most patients tested (2 in Italy and 22 in China so far). It is appreciated that the drug manufacturer Roche donated the equivalent of 2 million US dollars of Actemra to China.

Another promising result comes from the experimental drug remdesivir, which targets the replicative machinery of the virus. While our genome is made of DNA, SARS-CoV-2 (like other viruses) has a genome made of RNA, a variant of the genetic material. Therefore, the machinery that replicates viral RNA (called RNA polymerase) is different from the human one, and it can be selectively targeted with a drug. Remdesivir hampers the activity of the viral polymerase, and it has previously been tested with no side effects and somewhat encouraging results against Ebola and other viruses. Laboratory tests indicated that it might work efficiently also against SARS-CoV-2, and currently there are some phase 3 clinical trials on Covid-19 patients, to assess the effectiveness of the drug. The only available information so far comes from the USA and it’s about a 35-years-old patient that after remdesivir treatment improved his condition.

Another drug successfully tested is chloroquine, which is generally used to treat infections with intracellular micro-organisms (i.e.: malaria). In China it was discovered that chloroquine had a positive impact against the virus SARS-CoV-2, so it was immediately introduced in clinical trials. Chloroquine reduced the length of hospital stay and improved the evolution of Covid-19 pneumonia, making it another potential strategy. A weakness is that the biological function of chloroquine is still unknown, and this could result in unexpected side effects.

In this previous article I described the mechanism through which SARS-CoV-2 enters the cells. Shortly, the virus binds to a cell receptor (ACE2 receptor) through its Spike protein, which subsequently gets activated by the cell enzyme TMPRSS2 (like a pen needs the cap removed before writing) to allow the virus into the cell. Based on that information, the following potential strategies could be developed in the following months:

  1. a vaccine against the viral Spike protein. The organism would be exposed to a detuned Spike protein, stimulating the production of antibodies, but without causing the disease. Unfortunately, it is not possible to say if the immune memory will work against this virus.
  2. a drug that inhibits TMPRSS2-mediated activation of the Spike protein. A molecule able to block the enzyme TMPRSS2 would determine a milder infection.
  3. a drug that blocks ACE2 receptor. Blocking the anchor used by the virus to target a cell would slow down the infection.
  4. Excessive administration of soluble ACE2, to “distract” the virus from the real ACE2 receptor. This would slow down the infection, because many viral particles would bind to the fake receptor instead of entering a cell. Moreover, once infected a cell, the virus reduces the amount of ACE2 on the surface. Because ACE2 has anti-inflammatory, antioxidant and anti-fibrosis functions, extra-administration of soluble ACE2 would also protect the lungs from injury.

As we see, several approaches are currently being tested. Because clinical trials last for several weeks/months, it will take time before we have a definitive therapy against Covid-19. Anyway, we can be confident that if (or when) this virus will come back, we will ready to efficiently tackle it.

Sources

https://www.sciencedirect.com/science/article/pii/S0924857920300832

https://www.sciencedirect.com/science/article/pii/S1477893920300831

https://clinicaltrials.gov/ct2/show/NCT04257656

https://clinicaltrials.gov/ct2/show/NCT04252664

https://www.nejm.org/doi/10.1056/NEJMoa2001191

https://www.sciencedirect.com/science/article/pii/S0924857920300820

https://link.springer.com/article/10.1007/s00134-020-05985-9

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