The proof of concept is provided in the animal model of COVID: the candidate succeeds in preventing SARS-CoV-2 from binding to the ACE2 receptors that the virus uses to infect human cells. The drug locks onto the virus, then adds a “nitro group” to the ACE2 each time the virus approaches the receptor! In other words, the drug is harnessing the COVID-19 virus as a “harbinger” of its own doom.
The drug, named “NMT5” thus coats SARS-CoV-2 with chemicals
which directly and temporarily alter the human ACE2 receptor to which the virus is about to lock, to infect cells. This means that when the virus approaches, its way into human cells via the ACE2 receptor is blocked. The virus by announcing its arrival, prepares its own loss. But, at the same time, in the absence of the virus, the ACE2 receptors function normally.
“What’s so good about this drug is that we turn the virus against itself” says lead author Dr. Stuart Lipton, a professor at The Scripps “We arm it with small molecular warheads that eventually prevent it from infecting cells.”
The study: the team tests NMT5 in vitro on isolated cells as well as in vivo on animals and shows that:
- NMT5 attaches tightly to SARS-CoV-2 virus particles when the virus gets close enough to the cells to be infected;
- when the virus approaches ACE2, NMT5 adds a “nitro group” to the receptor;
- when ACE2 is changed in this way, its structure temporarily shifts so that the SARS-CoV-2 virus can no longer bind to it to cause infection.
“What is really beautiful”,
write the researchers, “is that it only reduces the availability of ACE2 locally and temporarily when the virus arrives. The drug does not inhibit all functions of ACE2 elsewhere in the body, which preserves the normal functioning of the protein” :
Proof of concept in vitro, in vivo and in the face of many variants:
- In vitro experiments, conducted on cell cultures with the objective of testing the ability of the Omicron variant of SARS-CoV-2 to bind to human ACE2 receptors, show that the candidate prevents 95% of viral binding;
- Preclinical Studies in Hamsters with COVID-19 Reveal that NMT5 Reduces Viral Load 100-fold, Eliminates Damage to Blood Vessels in Animals’ Lungs, and Calms Inflammation;
- the candidate also demonstrates efficacy against nearly a dozen other COVID-19 variants, including alpha, beta, gamma, and delta strains.
No risk of resistance: while most antivirals work by directly blocking part of a virus, which can put pressure on the virus to develop resistance to the drug, this is not the case for NMT5 which only uses the virus as carrier.
The team is currently working on a version suitable for human use, while continuing preclinical studies for safety and efficacy.
“This exciting work opens a new avenue for the development of more effective drugs in the face of the pandemic and the continued evolution of the virus.”