an already approved drug could eradicate all variants (by turning the virus against itself)

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Apart from vaccination, the means of combating COVID-19 are currently either symptomatic or intended for very specific forms of the disease. As the disease continues to evolve with the emergence of new variants, scientists are focusing their efforts on ways to treat it effectively. Since it profoundly affects the body down to the neurological level, researchers from the Scripps Research laboratory have turned to anti-influenza molecules, known to also act on neurological diseases. One of them, NMT5 (already approved by the FDA), has shown promising results against the virus. The compound literally turns the virus against itself and sends out “warheads” that alter the structure of the immune proteins it binds with to cause infection. The advantage? It could potentially target all variants of the virus as well as all forms of the disease.

For now, WHO recommendations for treating COVID are in favor of the nirmatrelvir/ritonavir combination. However, these antivirals would only concern patients at high risk of hospitalization (unvaccinated, immunocompromised, elderly patients, etc.) with mild and moderate forms. In addition to targeting only a portion of patients, these drugs have considerable shortcomings in terms of accessibility, particularly in low-income countries. For the latter, doctors sometimes continue to prescribe broad-spectrum antibiotics (azytrhomycin type), antimalarials and even homeopathic treatments.

Today, a few flu-like compounds have shown some effectiveness in countering the virus. However, these antivirals work more by blocking part of the virus and putting pressure on it, causing it to mutate and develop resistance. Since the COVID-19 virus, SARS-CoV-2, is also known to affect neurons, the researchers of the new study published in the journal Nature Chemical Biology explored the avenue of anti-influenza (memantine type), the latter having demonstrated in the past a certain effectiveness against certain neurological conditions, such as Parkinson’s.

My team had improved these antiviral drugs for the brain, and when COVID-19 emerged, we wondered if we had also, in the process, made one of them a better antiviral. “, explains the co-lead author of the study Stuart Lipton, professor at the Scripps Research Institute.

The best results have been observed with a compound called NMT5. The main advantage of the latter is that it uses the virus as a carrier of molecules modifying the structures of the ACE2 receptor (a key protein in the physiology of the coronavirus allowing it to penetrate host cells). This strategy would make it possible in particular to prevent any variant of the virus from infecting our body.

We expect this compound to continue to be effective even as new variants emerge, as it does not rely on attacking parts of the virus that typically mutate. says Chang-ki Oh, lead author of the new study and a researcher in the Departments of Molecular Medicine and Neuroscience at the Neurodegeneration New Medicines Center in La Jolla, USA. Another strong point: the molecule is already approved by the FDA, and its massive deployment could be easier than for other newly developed compounds.

Deliverers of nitrous warheads

To arrive at the selection of NMT5, the research team in the new study tested a wide range of memantine-like compounds, enhancing their structures with the help of nitroglycerin-like “ogives”. NMT5 can thus both bind to the surface of SARS-CoV-2 and modify the structure of ACE2 receptors thanks to nitrous derivatives, so that the virus is unable to bind to them and cause an infection.

Scripps Research’s NMT5 prevents SARS-CoV-2 (blue) from binding to ACE2 receptors (pink) to infect human cells. © Scripps Research

In single cell assays, modified NMT5 efficiently bound to viruses and added a group of nitrous molecules to ACE2 receptors when approaching them sufficiently. This structural change would have lasted for up to 12 hours, which is enough for the virus to not cause widespread infection. “ What is really beautiful is that it only reduces the availability of ACE2 locally when the virus arrives “says Lipton. According to the latter, the new drug only inhibits ACE2 locally, and does not affect their function elsewhere in the body.

By testing the compound on the Omicron variant of SARS-CoV-2, 95% of binding to host cells could be prevented. In hamsters, NMT5 reduced viral load 100-fold, prevented lung damage and reduced inflammatory responses. This effectiveness was also observed against a dozen other variants such as alpha, beta, gamma and delta. ” What’s so good about this drug is that we turn the virus against itself says Lipton. Currently, researchers are developing a version of the molecule that will soon be clinically tested. Additional toxicity and efficacy tests are also on the agenda.

Source: Nature Chemical Biology

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