Scripps Research Team Shows Variation of Already FDA-Approved Drug for Neurological Disease Can Block COVID-19 Infection in Animals ScienceDaily

drug, NMT5 nature chemical biology On September 29, 2022, SARS-CoV-2 will be coated with a chemical that can temporarily alter the human ACE2 receptor. This is the molecule that viruses normally latch onto in order to infect cells. That is, when the virus approaches, it blocks its pathway to human cells through the ACE2 receptor. However, if the virus is not present, ACE2 works normally.

“The beauty of this drug is that it actually turns the virus against itself,” said senior author Stuart Lipton, M.D., Ph.D., Step Family Endowed Chair and professor of Scripps Research. “We are arming it with small molecular warheads that will ultimately prevent it from infecting cells. That is our revenge on the virus.”

Before the COVID-19 pandemic, Lipton and his colleagues had long studied variations of memantine, a drug Lipton developed and patented in the 1990s to treat neurological disorders such as Alzheimer’s disease. . Memantine is derived from an anti-flu drug she used in the 1960s, but after noticing a woman whose Parkinson’s symptoms improved when she took her flu medication, clinicians began investigating other conditions. Did.

“My team made these antivirals better for the brain. When COVID-19 emerged, I wondered if I made any of them better antivirals in the process.” says Lipton.

Lipton and his team tested a library of compounds similar in overall structure to memantine but covered with additional pharmacological warheads. They demonstrated that a drug candidate, named NMT5, could recognize and bind to pores on the surface of SARS-CoV-2, and that it could chemically modify human ACE2 using fragments of nitroglycerin as warheads. identified as having two important characteristics. The group realized that this could turn the virus into a vehicle for its own demise.

In a new paper, Lipton’s group characterized and tested NMT5 in isolated cells and animals. They showed how NMT5 tightly attaches to SARS-CoV-2 virions as the virus moves through the body. and detailed how to add a chemical (like nitroglycerin). When he approaches ACE2 for the virus to infect cells, it is converted to NMT5, which adds a “nitro group” to the receptor. This modification of ACE2 causes a temporary change in its structure (about 12 hours) that prevents the SARS-CoV-2 virus from binding to it and causing infection.

“What’s really cool is that this only reduces the availability of ACE2 locally when the virus is close,” Lipton said. “He elsewhere in the body does not knock down all the functions of ACE2, but allows the normal function of this protein.”

In cell culture experiments testing how well the omicron mutant of SARS-CoV-2 can bind to the human ACE2 receptor, the drug prevented 95% of virus binding. It reduced viral levels 100-fold, eliminated vascular damage and ameliorated inflammation in the animal’s lungs. The drug also showed efficacy against nearly a dozen other His variants of COVID-19, including alpha, beta, gamma and delta strains.

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

“Because this compound doesn’t rely on attacking parts of the virus that normally mutate, we expect it to remain effective as new variants emerge,” said senior staff scientist and new Chang-ki Oh, lead author of the paper, said. .

Although they only studied the compound in animal models, the team is currently making a version of the drug to evaluate for human use while conducting additional safety and efficacy trials in animals. This work was sponsored by a National Institutes of Health (U19 AI171443) Scripps Center for Antivirals and Pandemic Response (CAMPP AViDD) grant.

“These exciting findings suggest new avenues in drug development that require drug combinations for effective pandemic preparedness,” said co-author Dr. Arnab Chatterjee.

In addition to Lipton, Oh and Chatterjee, the authors of the new paper are Tomohiro Nakamura, Nathan Beutler, Xu Zhang, Juan Piña-Crespo, Maria Talantova, Swagata Ghatak, Dorit Trudler, Lauren N. Carnevale, Scott R. McKercher and Malina A. is. Bakowski, Jolene K. Diedrich, Amanda J. Roberts, Ashley K. Woods, Victor Chi, Anil K. Gupta, Namir Shabani, Hejun Liu, Ian A. Wilson, Dennis R. Burton Mia A. Rosenfeld, Fiona L. Kearns, Lorenzo Casalino, and Romy E. Amaro of UCSD. and Cyrus Becker of EuMentis Therapeutics, Inc.

This work was supported by grants from the National Institutes of Health (RF1 AG057409, R01 AG056259, R01 DA048882, R35 AG071734 and DP1 DA041722, R01 AG061845, R61 PRAIRAND NS122098, R61 AM12298, support by R61 PRORIDAINOL). ), California Institute for Regenerative Medicine (DISC2 COVID19-11811), COVID-19 Award by Fast Grants, Bill & Melinda Gates Foundation (OPP1107194, INV-004923).

Lipton is the inventor of patents for the use of memantine and related compounds for neurodegenerative and neurodevelopmental disorders. He is also the inventor of composition and use patents for his NMT5-like aminoadamantane nitrate compounds in the treatment of COVID-19 and other viral diseases. Lipton holds the rights to these drugs.He is also the scientific founder of EuMentis Therapeutics, Inc.