New drug can turn Covid virus against itself and fight its variants

US scientists have developed a new drug that can turn SARS-CoV-2 against itself and prevent the deadly virus from infecting humans.

Researchers at The Scripps Research Institute believe the drug, called NMT5, may be effective against emerging variants of SARS-CoV-2.

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The drug, described in the journal Nature Chemical Biology, coats SARS-CoV-2 with chemicals that can temporarily alter the human ACE2 receptor, the molecule that the virus normally latches onto to infect cells.

When the virus is nearby, its pathway into human cells via the ACE2 receptor is blocked. In the absence of the virus, however, ACE2 can function as usual, the researchers said.

The nice thing about this drug is that we’re actually turning the virus against itself,” said the study’s lead author, Stuart Lipton, a professor at The Scripps Research Institute.

The team tested a library of compounds and determined that NMT5 had two key properties: it could recognise and bind to a pore on the surface of SARS-CoV-2, and chemically modify human ACE2 using a nitroglycerin fragment as a warhead.

The researchers realised that this could turn the virus into a delivery vehicle for its own demise.
They characterised and tested NMT5 in isolated cells and in animals. The study showed how NMT5 binds tightly to SARS-CoV-2 viral particles as the viruses move through the body.

The researchers then revealed the details of how the drug adds a chemical, similar to nitroglycerin, to certain molecules if it gets close enough. When the virus gets close enough to ACE2 to infect a cell, that translates into NMT5 adding a “nitro group” to the receptor. When ACE2 is modified in this way, its structure changes temporarily – for about 12 hours – so that the SARS-CoV-2 virus can no longer bind to it to cause infection. “The beauty is that this only reduces the availability of ACE2 locally when the virus gets close to it. It doesn’t eliminate the entire function of ACE2 elsewhere in the body, which allows normal functioning of this protein,” Lipton said.

In cell culture experiments testing the ability of the Omicron variant of SARS-CoV-2 to bind to human ACE2 receptors, the drug prevented 95% of viral binding.

In hamsters with COVID-19, NMT5 reduced virus levels by 100-fold, eliminated damage to blood vessels in the animals’ lungs and improved inflammation, the researchers said.

The drug also proved effective against nearly a dozen other variants of the virus, including Alpha, Beta, Gamma and Delta strains, they said.

Most antiviral drugs work by directly blocking part of the virus, which can push it to develop resistance to the drug.
Because NMT5 only uses the virus as a carrier, the researchers believe the drug is likely to be effective against many other SARS-CoV-2 variants.

“We expect that this compound will remain effective even when new variants emerge, because it does not rely on targeting parts of the virus that often mutate,” said Chang-ki Oh, lead scientist and first author of the research.

Although the researchers have only studied the compound in animal models, they are now manufacturing a version of the drug to evaluate its use in humans, while conducting additional safety and efficacy trials in animals.

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