A new use for an old drug has the potential to turn the virus against itself according to a new study by the US based Scripps Research Institute.
The drug, NMT5, described in Nature Chemical Biology on 29 September 2022, coated COVID with chemicals that could temporarily alter the human ACE2 receptor—the molecule the virus normally latches onto to infect cells.
Memantine, from which NMT5 is derived, is already an FDA-approved therapeutic for neurological disease that has been shown to block COVID infection in animals, and the tweak by scientists at Scripps Research could turn COVID into a harbinger of its own doom.
Senior author and Scripps Researcher, Professor Stuart Lipton, explained that when the virus was near, its path into human cells via the ACE2 receptor was blocked; but when COVID was absent, the ACE2 receptor could function normally.
“What’s so neat about this drug is that we’re actually turning the virus against itself,” Professor Lipton said.
“We’re arming it with little molecular warheads that end up preventing it from infecting our cells – it’s our revenge on the virus.”
In cell culture experiments with the Omicron variant NMT5 prevented 95% of viral binding, and in hamsters infected with COVID, the drug decreased virus levels by 100-fold, eliminated blood vessel damage in the animals’ lungs, and ameliorated inflammation.
Most anti-viral drugs work by directly blocking part of a virus – which can pressure the virus to evolve resistance to the drug – but as NMT5 is only using the virus as a carrier and does not rely on attacking parts of the virus that commonly mutate, the researchers think the drug is also likely to be effective against many other variants.
Testing showed effectiveness against nearly a dozen other variants of COVID, including alpha, beta, gamma, and delta strains thanks to its unique characteristics.
Before the pandemic, Lipton and his colleagues had been studying variations of the drug memantine, which Lipton developed and patented in the 1990s for treating neurological diseases like Alzheimer’s.
While memantine originated from an anti-influenza drug used in the 1960s, clinicians began investigating it for additional diseases after they noticed a woman with Parkinson’s symptoms improved when she took the drug for the flu.
“My team had made these antiviral drugs better for the brain, and when COVID emerged, we wondered whether we had also, in the process, made any of them better antivirals,” Professor Lipton explained.
Lipton and his team tested a library of compounds similar to memantine in overall structure but covered with additional pharmacological warheads.
They ended up pinpointing the drug candidate designated NMT5 as having two key properties: it could recognize and attach to a pore on the surface of COVID, and it could chemically modify human ACE2 using a fragment of nitro-glycerine as the warhead.
The group realized this could turn the virus into a delivery vehicle for its own demise.
Tests in isolated cells and animals demonstrated that NMT5 attaches tightly to COVID viral particles as they move through the body, adding a chemical (similar to nitro-glycerine) to certain molecules if it gets close enough.
When the virus gets near ACE2 to infect a cell, NMT5 adds a “nitro group” to the receptor, temporarily shifting its structure for about 12 hours so that the virus can no longer bind to it to cause infection.
“What’s really beautiful is that this only knocks down availability of ACE2 locally when the virus is coming at it,” Professor Lipton said.
“It doesn’t knock down all the function of ACE2 elsewhere in the body, allowing for normal function of this protein.”
Though they have only studied the compound in animal models, the team is now making a version of the drug to evaluate for human use, while carrying out additional safety and effectiveness trials in animals.