Team of researchers led by PD Dr. Marcel Mller of Charit’s Institute of Virology and Dr. Nils Gassen of the Psychiatry and Psychotherapy Clinic and Outpatient Clinic at the University Hospital Bonn (UKB) have investigated the way in which SARS-CoV-2 reprograms host cells for its own benefit.

They concluded that the new coronavirus slows down the cell’s own recycling mechanism, a process known as autophagy. The purpose of this ‘auto-digestion’ mechanism is to enable the cell to dispose of damaged cell materials and waste products while recycling usable molecular building blocks for incorporation into new cellular structures.

“In our study, we were able to show that at the same time as using the cell’s building blocks for its own benefit, SARS-CoV-2 deceives the cell by simulating a nutrient-rich status, thereby slowing cellular recycling,” explains first author Dr. Gassen.

As part of this work, the researchers undertook a detailed analysis of SARS-CoV-2 infected cells and the lung tissue of COVID-19 patients, studying cellular metabolism and the processing of molecular signals. “It is likely that SARS-CoV-2 uses this to avoid dismantling by the cell.

After all, viruses are also subject to autophagic disposal,” adds the study’s last author, DZIF researcher PD Dr. Mller. He adds: “The same reprogramming strategy is also used by the MERS coronavirus, whose autophagy-inhibiting action we were able to demonstrate more than a year ago. However, there are other coronaviruses which, quite in contrast to this, induce autophagy. These mainly infect animals.”

Recycling mechanism might be a potential target for COVID-19 therapy, the researchers tested whether substances which induce cellular recycling also reduce the replication of SARS-CoV-2 inside infected cells.

Spermine is found in wheat germ, soya, mushrooms, and mature cheese and is freely available as a food supplement. When the researchers added spermidine to cells infected with SARS-CoV-2, this resulted in an 85 percent reduction in the numbers of virus particles produced.

This derivative of spermidine was found to reduce viral replication by more than 90 percent in human lung cells and in a human gut model comprising clusters of cells known as ‘organoids’.

“The obvious effects produced by spermidine and, in particular, spermine are certainly encouraging. For one thing, substances which occur naturally in the body are less likely to induce side effects,” says PD Dr. Mller.

“Having said that, we worked with pure forms of these substances which are not suitable for medical use. Spermidine, in particular, has to be used at relatively high concentrations to achieve an appreciable effect in cell culture.

Self-medication is not advisable, one of the reasons being that viruses also use polyamines to help boost replication; the correct dosage is therefore crucial. The same applies to fasting, which can stimulate the body’s autophagy process. Given that the body needs energy to mount an immune response, it remains unclear whether fasting is advisable in SARS-CoV-2 infected patients.”

The third substance to prove effective against SARS-CoV-2 was the ‘AKT inhibitor’ MK-2206. The substance is currently at the clinical trial stage. MK-2206 reduced the production of SARS-CoV-2 virus by around 90%.

“Based on our data, I would consider MK-2206 as an interesting treatment candidate against COVID-19 which, after a careful analysis of risks and benefits, would justify further study in clinical trials,” explains PD Dr. Mller.

Niclosamide found to be more effective against the MERS coronavirus during an earlier 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.

What is more, it has been licensed for use against tapeworm infections in humans for a very long time and is well tolerated at potentially relevant doses,” says PD Dr. Mller. He adds: “Out of the four new candidate substances, we consider it to be the most promising one.

This is why we are now conducting a clinical trial at Charit to test whether niclosamide might also have a positive effect on people with COVID-19. I am delighted at this development. It shows how quickly findings from basic research can reach patients if research and clinical practice are closely interlinked and work together in an efficient manner.”

The Phase II clinical trial – entitled ‘NICCAM’ – is being led by Prof. Dr. Martin Witzenrath, Deputy Head of Charit’s Department of Infectious Diseases and Respiratory Medicine.

The study will test the safety, tolerability, and efficacy of niclosamide combined with camostat (another licenced drug) in patients recently (within the last few days) diagnosed with COVID-19. The study is currently recruiting and looking for participants.

Source: Medindia