2023-08-31 22:02:50
01.09.2023
AIDS, the flu, COVID-19 – once more and once more viral infections overwhelm entire regions of the world and cost lives. To date, there are no drugs with a broad antiviral effect.
Researchers from Hanover want to change that: In the journal PLOS Pathogens, Prof. Frank Peßler and his team at TWINCORE – Center for Experimental and Clinical Infection Research, a joint facility of the Helmholtz Center for Infection Research and the Hannover Medical School, describe a way of propagating a wide variety of effective in inhibiting viruses.
For the study that has now been published, the researchers from the Biomarkers for Infectious Diseases working group worked together with teams from the Universities of Gießen and Aarhus and the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS). The project was funded in the COVID-Protect program of the Federal Ministry of Education and Research (BMBF).
Therapeutic targets in humans
The fact that it is so tricky to fight viruses is partly due to their simple structure. They offer only a few points of attack for inhibiting active substances. In addition, they change once more and once more in such a way that active ingredients no longer recognize their target. The viruses, which consist of just a few components, use the body’s own structures in their host, for example humans, to reproduce.
Also because severe effects of a viral infection are often due to an excessive reaction of the immune system, researchers are increasingly turning their attention to the interaction of the virus, human physiology and the immune system. The aim is to find mechanisms in the body that can be therapeutically inhibited or enhanced in order to slow down a viral infection and alleviate its effects. The researchers led by Frank Peßler have now succeeded in influencing two mechanisms in human cells at the same time in such a way that both occur.
Right drug, unexpected mechanism
Peßler and his team are researching the endogenous molecule itaconic acid. Some time ago, they discovered that a pharmacologically optimized variant of it, 4-octyl itaconate, is particularly efficient in activating a signaling pathway that controls various protective and defense mechanisms in human cells. The switch for this signaling pathway is a protein called NRF2. Again and once more, their experiments also provided evidence that 4-octyl itaconate directly affects virus replication – independent of the NRF2 signaling pathway. To follow up on these clues, they produced cells without the NRF2 protein in the laboratory. If the circuit breaker was missing, influenza viruses actually multiplied better.
To their surprise, however, the researchers found that even without NRF2, 4-octyl itaconate inhibits the multiplication of the flu virus just as strongly as in unmodified cells. “When we saw the first results of these tests, we were amazed,” says Frank Pessler. “Apparently we had been investigating the right active ingredient the whole time, but only now have we discovered the key mechanism of action.”
Transport route blocked
Pessler and his colleagues suspected that 4-octyl itaconate impeded the transport of proteins and nucleic acids from the cell nucleus, on which many viruses depend. To test their assumption, they compared the effect of 4-octyl itaconate with that of a cancer drug (Selinexor), which blocks a transport channel from the cell nucleus. Both the cancer drug and the itaconic acid variant inhibited the replication of an influenza virus. They prevented the precursors of the newly formed virus particles from being transported out of the nucleus of the host cell. The unfinished viruses got stuck in the cell nucleus, so to speak.
“We were very surprised how efficiently 4-octyl itaconate directly inhibits the replication of influenza viruses through this mechanism,” says Pessler. The authors of the current study also provide an explanation for their observation: they found a point in the structure of the transport channel to which both 4-octyl itaconate and the cancer drug bind. It resembles where 4-octyl itaconate interacts with the protein that controls the NRF2 switch. Using biochemical methods, the researchers were able to prove that 4-octyl itaconate actually binds to the nuclear transporter in human cells and thereby blocks it. Pessler and his colleagues also observed this effect with other substances that were previously only known as NRF2 activators.
Potential for broad effectiveness
The findings that have now been published open up new perspectives for the development of antiviral therapies. Interestingly, a wide variety of viruses with very different life cycles depend on the export of proteins or nucleic acids from the nucleus. From the influenza virus, which causes seasonal flu, and SARS-CoV-2 to the respiratory syncytial virus (RSV), which brought numerous small children to the hospital last winter, to rabies, which is widespread in many Asian and African (travel) countries more widespread once more – they all need the transport channel to reproduce. With different viruses, different steps of propagation depend on the channel. Blocking this pathway therefore promises to counteract many different types of viruses.
Slow down viruses, protect cells
Newly emerging viruses might possibly be slowed down in this way. “The next pandemic will definitely come,” says Frank Pessler. “And wouldn’t it be nice to have a pill that can help people quickly and stop the spread early – even before you know exactly what virus it is?”
The fact that an inhibitor of the transport channel has already been approved as a drug opens up prospects for a speedy adaptation of the therapy to viral infections. However, this drug does not have the cell-protecting properties of the NRF2 activators. Pessler is therefore planning to optimize chemical variants of itaconic acid in such a way that they have both virus-inhibiting and cell-protecting effects. The fact that itaconic acid is of endogenous origin gives reason to hope that drug candidates will emerge with as few undesirable side effects as possible.
Those: TWINCORE, Center for Experimental and Clinical Infection Research
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