Science

COVID: Already approved drug could wipe out all variants (by turning the virus against itself)

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In addition to vaccination, the means to combat COVID-19 are currently either symptomatic or targeted for very specific forms of the disease. As the disease continues to evolve with new variants emerging, scientists are focusing their efforts on ways to treat it effectively. Because it deeply affects the body down to the neurological level, researchers at the Scripps Research Laboratory turned to anti-flu 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 to, causing infection. Advantage? It could potentially target all variants of the virus, as well as all forms of the disease.

For now, WHO recommendations for COVID treatment favor the nirmatrelvir/ritonavir combination. However, these antivirals would only apply to patients at high risk of hospitalization (unvaccinated, immunocompromised, elderly patients, etc.) with mild to moderate forms. In addition to being limited to a subset of patients, these drugs have significant disadvantages in terms of availability, especially in low-income countries. In the latter case, doctors sometimes continue to prescribe broad-spectrum antibiotics (such as azithromycin), antimalarial drugs, and even homeopathic remedies.

Today, several flu-like compounds have shown some effectiveness in fighting 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. Because the COVID-19 virus, SARS-CoV-2, is known to infect neurons, researchers in a new study published in the journal Nature Chemical Biology have explored the possibility of an anti-influenza (memantine) action that has been shown in the past to have some efficacy against certain neurological conditions. such as Parkinson’s disease.

“My team improved these antivirals for the brain, and when COVID-19 came along, we wondered if we had made one of them a more effective antiviral in the process,” says study co-author Stuart Lipton. professor at the Scripps Research Institute.

The best results were obtained with a compound called NMT5. The main advantage of the latter is that it uses the virus as a carrier of molecules that modify the structures of the ACE2 receptor (a key protein in the physiology of the coronavirus that allows it to enter host cells). This strategy would, in particular, prevent infection of our body with any variant of the virus.

“We expect this compound to remain effective even as new variants emerge because it does not depend on the attacking parts of the virus, which would normally mutate,” says Chang-ki Oh, lead author of the novel. molecular medicine and neuroscience at the Center for New Drugs for Neurodegeneration in La Jolla (USA). Another strong point: The molecule is already FDA-approved, and its mass adoption may be easier than for other recently developed compounds.

Nitrogen Warhead Suppliers

To arrive at the choice of NMT5, the research team in a new study tested a wide range of memantine-like compounds, improving their structure with nitroglycerine-like “ozhives”. Thus, NMT5 can both bind to the surface of SARS-CoV-2 and change the structure of ACE2 receptors due to nitrogenous derivatives, so that the virus cannot bind to them and cause infection.

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

In single cell studies, modified NMT5 effectively binds to viruses and adds a group of nitrogen molecules to ACE2 receptors when close enough to them. This structural change would last up to 12 hours, which is long enough for the virus not to cause widespread infection. “What’s really great is that it just reduces the availability of ACE2 locally when a virus appears,” Lipton notes. According to the latter, the new drug only inhibits ACE2 locally and does not affect their function in other parts of the body.

When testing the compound on the SARS-CoV-2 Omicron variant, 95% of binding to host cells could be prevented. In hamsters, NMT5 reduced viral load by 100-fold, prevented lung damage, and reduced inflammatory responses. This efficiency has also been observed with a dozen other variants such as alpha, beta, gamma, and delta. “What’s great about this drug is that we’re turning the virus against itself,” says Lipton. The researchers are currently developing a version of the molecule that will soon enter clinical trials. Additional toxicity and efficacy tests are also on the agenda.

Chemical biology of nature.

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