A tapeworm drug against SARS-CoV-2? Clinical study to test potential new treatments

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Researchers at the German Center for Infection Research (DZIF) at Charité – Universitätsmedizin Berlin and the University of Bonn have examined how SARS-CoV-2 reprogrammes the host cell’s metabolism in order to achieve an overall benefit. According to her report in Nature communication, the researchers were able to identify four substances that inhibit SARS-CoV-2 replication in the host cell: spermine and spermidine, the body’s own substances; MK-2206, an experimental cancer drug; and niclosamide, a tapeworm drug. The Charité is currently conducting a study to determine whether niclosamide is also effective against COVID-19 in humans.

Viral replication depends on the host cell’s machinery and the use of the host’s molecular building blocks. In order to avoid detection by the immune system, viruses must also ensure that they can evade cellular surveillance systems. To do this, they manipulate various processes in the infected host cell – and each virus follows a different strategy. A research team led by PD Dr. Marcel Müller from the Institute for Virology at the Charité and Dr. Nils Gassen from the Clinic and Outpatient Clinic for Psychiatry and Psychotherapy at the University Hospital Bonn (UKB) has therefore examined how SARS-CoV -2 reprogrammes host cells for its own benefit. Their most important finding was: The new coronavirus slows down the cell’s own recycling mechanism, the so-called autophagy. The purpose of this ‘self-digesting’ mechanism is to enable the cell to dispose of damaged cell material and waste products, while at the same time recycling usable molecular building blocks for incorporation into new cell structures.

“In our study we were able to show that SARS-CoV-2 simultaneously with the use of the building blocks of the cell for its own benefit deceives the cell by simulating a nutrient-rich state and thus slowing down cell recycling,” explains author Dr. Alleys. As part of this work, the researchers carried out a detailed analysis of SARS-CoV-2 infected cells and the lung tissue of COVID-19 patients, examined cell metabolism and the processing of molecular signals. “It is likely that SARS-CoV-2 uses this to avoid degradation by the cell. After all, viruses are also subject to autophagous disposal, ”adds the last author of the study, DZIF researcher PD Dr. Müller. He adds: “The same reprogramming strategy is also used with the MERS coronavirus, whose autophagy-inhibiting effects we were able to demonstrate more than a year ago. However, there are other coronaviruses that, in contrast, induce autophagy mainly infect animals. “

When the results of the study suggested that the recycling mechanism could be a potential target for COVID-19 therapy, the researchers tested whether substances that induce cell recycling also reduce the replication of SARS-CoV-2 in infected cells. Interestingly, the researchers found four substances that were found to be effective – all of which have already been used in humans. These included the polyamine spermidine, an autophagy-enhancing metabolite that is produced in all human cells and by bacteria in the human intestine. It occurs naturally in foods such as wheat germ, soy, mushrooms, and mature cheese and is freely available as a dietary supplement. When the researchers added spermidine to cells infected with SARS-CoV-2, it resulted in an 85 percent reduction in the number of virus particles produced. Similar results have been obtained with spermine, another polyamine that occurs naturally in the body. This spermidine derivative was found to reduce virus replication by more than 90 percent in human lung cells and in a human intestinal model that includes cell clusters known as “organoids”.

“The obvious effects of spermidine, and spermine in particular, are certainly encouraging. On the one hand, the body’s own substances cause fewer side effects, ”says PD Dr. Müller. “However, we worked with pure forms of these substances that are not suitable for medical use. In particular, spermidine must be used in relatively high concentrations in order to achieve a noticeable effect in cell culture. So many questions remain unanswered. ”Before we can consider polyamines as a potential treatment for COVID-19, will it be possible, when used in the body, to achieve blood levels high enough to inhibit virus replication in the airways? And if so, would it be administered before or during the Is an infection advisable? Are there any side effects? Nevertheless, our findings from cell culture are a good starting point for research with animal models. Self-medication is not advisable, also because viruses use polyamines to encourage reproduction; therefore the correct dosage is crucial. The same goes for fasting, which can stimulate the body’s autophagy. Since the body needs energy to build an immune response, it remains unclear whether fasting is advisable in SARS-CoV-2 infected patients. “

The third substance that was found to be effective against SARS-CoV-2 was the “AKT inhibitor” MK-2206. The substance is currently in the clinical trial phase and is being tested for its tolerance and effectiveness against various types of cancer. In the current study, MK-2206 reduced the production of the infectious SARS-CoV-2 virus by about 90%. This was done at plasma concentrations that had already been reached in a previous study. “Based on our data, I would consider MK-2206 as an interesting treatment candidate for COVID-19, which, after a careful risk-benefit analysis, would justify further studies in clinical trials,” explains PD Dr. Müller.

The strongest antiviral effect has been linked to niclosamide, which the researchers had shown to be effective against the MERS coronavirus in a previous study. The tapeworm drug was found to reduce the production of infectious SARS-CoV-2 particles by more than 99 percent. “Niclosamide showed the strongest effect in our cell culture-based experiments. In addition, it has been approved for use against tapeworm infections in humans for a very long time and is well tolerated in potentially relevant doses, ”says PD Dr. Müller. He adds: “Of the four new drug candidates, we think it is the most promising. That is why we are now conducting a clinical study at the Charité to test whether niclosamide could also have a positive effect on people with COVID-19. I am very pleased with this development. It shows how quickly findings from basic research reach patients when research and clinical practice are closely linked and work together efficiently. “

The clinical phase II study with the title “NICCAM” is being led by Prof. Dr. Martin Witzenrath, Deputy Head of the Clinic for Infectious Diseases and Respiratory Medicine at the Charité. The study will test the safety, tolerability and effectiveness of niclosamide in combination with Camostat (another approved drug) in patients recently (within the last few days) diagnosed with COVID-19.



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