Californian Researchers Modify Generic Drug Memantine To Inhibit SARS-CoV-2 And Treat COVID-19 Issues
: Researchers from Scripps Research Institute - California-USA have created a variant of the generic drug Memantine which is an Aminoadamantane compound, to inhibit the SARS-CoV-2 virus entry by targeting the ACE2 receptors.
Prevention of infection and propagation of the SARS-CoV-2 coronavirus is a high priority in the ongoing COVID-19 pandemic which is expected to get worse.
The study team utilized the process of S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin-converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 spike protein, thereby inhibiting viral entry, infectivity and cytotoxicity.
Aminoadamantane compounds such as memantine pharma variants also inhibit coronavirus ion channels formed by envelope (E) protein.
The COVID-19 Drugs
research team developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and, thus, the spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E protein channel blockade.
The study findings showed that these non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model and, thus, provide a novel avenue to pursue therapy. The team is next panning clinical studies to test the efficacy of the new drug after animal safety studies have already demonstrated no adverse effects plus the fact that memantine has been a U.S FDA approved drug for more than 19 years now with a good safety track record.
The team has temporarily named the new antiviral products as NMT5.
The study findings were published in the peer reviewed journal: Nature Chemical Biology. https://www.nature.com/articles/s41589-022-01149-6
Memantine is a oral generic medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is believed to work by blocking NMDA receptors.
Memantine was approved for medical use in the United States in 2003. In 2019, it was the 169th most commonly prescribed medication in the United States, with more than 3 million prescriptions.
Besides being used as drug to treat moderate-to-severe Alzheimer's disease and Dementia, it is also being investigated or use in Autism and also in Parkinson disease.
The drug has also numerous pharmacological benefits that also aids in treating the various issues that develop during COVID-19 infections including the suppression of various inflammatory pathways that are triggered in COVID-19.
The study is the first to demonstrate that this new memantine variant may prevent COVID-19 infection in animals.
According to the study team, the new drug NMT5 may make the SARS-CoV-2 virus into a harbinger of its own doom.
The study team says that the drug coats SARS-CoV-2 with chemicals that may temporarily modify the human ACE2 receptor- the molecule the virus normally latches onto to infect cells. That means that while the viru
s is nearby, its entry into human cells through the ACE2 receptor is inhibited; however, when the virus is not there, ACE2 may operate normally.
Senior author Dr Stuart Lipton, MD, Ph.D., the Step Family Endowed Chair and Scripps Research professor said, “What’s so neat about this drug is that we’re actually turning the virus against itself. We’re arming it with little molecular warheads that end up preventing it from infecting our cells; it’s our revenge on the virus.”
The study team have long been researching variations of the drug memantine, which Dr Lipton created and patented in the 1990s for treating neurological diseases such as Alzheimer’s. While memantine originated from an anti-influenza drug in the 1960s, clinicians began looking into it for other disorders after seeing a woman with Parkinson’s symptoms improve when she took the drug for the flu.
Dr Lipton added, “My research 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.”
The study team Lipton tested a library of compounds with overall structures comparable to memantine but with additional pharmacological warheads. They identified NMT5 as a drug candidate with two critical properties: it could detect and attach to a pore on the surface of SARS-CoV-2, and it could chemically modify human ACE2 using a nitroglycerin fragment as the warhead. The team realized that this could transform the virus into a vehicle for its own destruction.
The study team characterized and tested NMT5 in isolated cells as well as animals.
The study findings demonstrated how NMT5 attaches tightly to SARS-CoV-2 viral particles as the viruses move through the body.
Subsequently, the study findings reveal the details of how the drug adds a chemical (similar to nitroglycerin) to certain molecules if it gets close enough.
Interestingly, when the SARS-CoV-2 virus gets near ACE2 to infect a cell, that makes the NMT5 to add a “nitro group” to the receptor. When ACE2 is modified in this way, its structure temporarily shifts for about 12 hours so that the SARS-CoV-2 virus can no longer bind to it to cause infection.
Dr Lipton explained, “What’s really beautiful is that this only knocks down the availability of ACE2 locally when the virus is coming at it. It doesn’t knock down all the function of ACE2 elsewhere in the body, allowing for the normal function of this protein.”
Importantly, in cell culture experiments testing how well the Omicron variant of SARS-CoV-2 can attach to human ACE2 receptors, the drug prevented 95% of viral binding. In hamsters with COVID-19, NMT5 decreased virus levels by 100-fold, eliminated blood vessel damage in the animals’ lungs, and ameliorated inflammation. The drug also showed effectiveness against nearly a dozen other variants of COVID-19, including alpha, beta, gamma, and delta strains.
Typically, most antiviral drugs work by directly blocking part of a virus which can pressure the virus to evolve resistance to the drug.
However, since NMT5 is only using the virus as a carrier, the study team think the drug is likely to be effective against many other variants of SARS-CoV-2.
Dr Chang-ki Oh, a senior staff scientist and first author of the new paper explained, “We expect this compound would continue to be effective even as new variants emerge because it doesn’t rely on attacking parts of the virus that commonly mutate.”
Although the study team has 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.
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however remains skeptical of any antivirals being developed in the United States due to the track record of the US FDA and also the long-term adverse effects of such drugs. To date, the U.S. FDA had approved a variety of highly toxic drugs to treat COVID-19 such as remdesivir, paxlovid and molnupiravir, all with little or no success.
The answer to effective COVID-19 prophylactics and therapeutics lie in the various phytochemicals that nature has blessed us with.
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