A new drug designed by scientists at Scripps Research can turn the COVID-19 virus into a harbinger of its own doom.
The drug, NMT5, described in Nature Chemical Biology on September 29, 2022, coats SARS-CoV-2 with chemicals that can temporarily alter the human ACE2 receptor — the molecule the virus normally latches onto to infect cells. That means that when the virus is near, its path into human cells via the ACE2 receptor is blocked; in the absence of the virus, however, ACE2 can function as usual.
“What’s so neat about this drug is that we’re actually turning the virus against itself,” says senior author Stuart Lipton, MD, PhD, the Step Family Endowed Chair and Scripps Research professor. “We’re arming it with little molecular warheads that end up preventing it from infecting our cells; it’s our revenge on the virus.”
Before the COVID-19 pandemic, Lipton and his colleagues had long 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-19 emerged, we wondered whether we had also, in the process, made any of them better antivirals,” says Lipton.
Lipton and his team tested a library of compounds similar to memantine in overall structure but covered with additional pharmacological warheads. They pinpointed the drug candidate designated NMT5 as having two key properties: It could recognize and attach to a pore on the surface of SARS-CoV-2, and it could chemically modify human ACE2 using a fragment of nitroglycerin as the warhead. The group realized this could turn the virus into a delivery vehicle for its own demise.
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