New Antiviral Nasal Spray Outperforms Current Antibody Treatments for COVID-19 and Its Variants in Mice

A single inhaled dose treated or even prevented infection by COVID-19 and its variants.

Current antibody treatments block SARS-CoV-2 by binding to one of three binding sites on the spike protein

New antiviral binds to all three sites on the spike protein, making it more effective than current therapies

Antiviral is also low-cost, easy to manufacture, does not require complicated supply chains with extreme refrigeration and potentially could be self-administered

A new protein-based antiviral nasal spray developed by researchers at Northwestern University, University of Washington and Washington University at St. Louis is being advanced toward Phase I human clinical trials to treat COVID-19.

Designed computationally and refined in the laboratory, the new protein therapies thwarted infection by interfering with the virus’ ability to enter cells. The top protein neutralized the virus with similar or greater potency than antibody treatments with Emergency Use Authorization status from the U.S. Food and Drug Administration (FDA). Notably, the top protein also neutralized all tested SARS-CoV-2 variants, something that many clinical antibodies have failed to do.

When researchers administered the treatment to mice as a nasal spray, they found that the best of these antiviral proteins reduced symptoms of infection — or even prevented infection outright.

CryoEM image of the novel coronavirus’ spike protein. Credit: Northwestern University/Washington University/University of Washington

The findings were published on April 12, 2022, in the journal Science Translational Medicine.

This work was led by Northwestern’s Michael Jewett; David Baker and David Veesler at the University of Washington School of Medicine; and Michael S. Diamond at WashU.

To begin, the team first used supercomputers to design proteins that could stick to vulnerable sites on the surface of the novel coronavirus, targeting the spike protein. This work was originally reported in 2020 in the journal Science.

In the new work, the team reengineered the proteins — called minibinders — to make them even more potent. Rather than targeting just one site of the virus’ infectious machinery, the minibinders simultaneously bind to three sites, making the drug less likely to detach.

CryoEM image of the novel coronavirus’ spike protein. From this top-down angle, you can see the three binding sites on the protein. Credit: Northwestern University/Washington University/University of Washington

“SARS-CoV-2’s spike protein has three binding domains, and common antibody therapies may only block one,” Jewett said. “Our minibinders sit on top of the spike protein like a tripod and block all three. The interaction between the spike protein and our antiviral is among the tightest interactions known in biology. When we put the spike protein and our antiviral therapeutic in a test tube together for a week, they stayed connected and never fell apart.”

Jewett is a professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and director of Northwestern’s Center for Synthetic Biology. Andrew C. Hunt, a graduate research fellow in Jewett’s laboratory, is the paper’s co-first author.

As the SARS-CoV-2 virus has mutated to create new variants, some treatments have become less effective in fighting the ever-evolving virus. Just last month, the FDA paused several monoclonal antibody treatments, for example, due to their failure against the BA.2 omicron subvariant.

Unlike these antibody treatments, which failed to neutralize omicron, the new minibinders maintained potency against the omicron variant of concern. By blocking the virus’ spike protein, the new antiviral prevents it from binding to the human angiotensin-converting enzyme 2 (ACE2) receptor, which is the entry point for infecting the body. Because the novel coronavirus and its mutant variants cannot infect the body without binding to the ACE2 receptor, the antiviral also should work against future variants.

“To enter the body, the spike protein and ACE2 receptor engage in a handshake,” Jewett said. “Our antiviral blocks this handshake and, as a bonus, has resistance to viral escape.”

In addition to losing effectiveness, current antibody therapies also come with several problems: They are difficult to develop, expensive and require a healthcare professional to administer. They also require complicated supply chains and extreme refrigeration, which is often unavailable in low-resource settings.

The new antiviral solves all these problems. As opposed to monoclonal antibodies, which are made by cloning and culturing living mammalian cells, the new antiviral treatment is produced large-scale in microorganisms like E. coli, making them more cost-effective to manufacture. Not only is the new therapy stable in high heat, which could further streamline manufacturing and decrease the cost of goods for clinical development, it also holds promise for being self-administered as a one-time nasal spray, bypassing the need for medical professionals.

The researchers imagine that it could be available at the pharmacy and used as a preventative measure to treat infections.

Reference: “Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice” by Andrew C. Hunt, James Brett Case, Young-Jun Park, Longxing Cao, Kejia Wu, Alexandra C. Walls, Zhuoming Liu, John E. Bowen, Hsien-Wei Yeh, Shally Saini, Louisa Helms, Yan Ting Zhao, Tien-Ying Hsiang, Tyler N. Starr, Inna Goreshnik, Lisa Kozodoy, Lauren Carter, Rashmi Ravichandran, Lydia B. Green, Wadim L. Matochko, Christy A. Thomson, Bastian Vögeli, Antje Krüger, Laura A. VanBlargan, Rita E. Chen, Baoling Ying, Adam L. Bailey, Natasha M. Kafai, Scott E. Boyken, Ajasja Ljubetic, Natasha Edman, George Ueda, Cameron M. Chow, Max Johnson, Amin Addetia, Mary Jane Navarro, Nuttada Panpradist, Michael Gale, Benjamin S. Freedman, Jesse D. Bloom, Hannele Ruohola-Baker, Sean P. J. Whelan, Lance Stewart, Michael S. Diamond, David Veesler, Michael C. Jewett and David Baker, 12 April 2022, Science Translational Medicine.

This study, “Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice,” was supported by:

Howard Hughes Medical Institute, including a fellowship from the Damon Runyon Cancer Research Foundation;

Department of Defense (NDSEG-36373, W81XWH-21-1-0006, W81XWH-21-1-0007, W81XWH-20-1-0270-2019, AI145296, and AI143265);

Defense Advanced Research Project Agency (HR0011835403 contract FA8750-17-C-0219);

National Institutes of Health (1P01GM081619, R01GM097372, R01GM083867, T32GM007270, S10OD032290);

National Institute of Allergy and Infectious Diseases (DP1AI158186, HHSN272201700059C, R37 AI1059371, R01 AI145486);

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK117914, R01DK130386, U01DK127553, F31DK130550);

and with federal funds from the Department of Health and Human Services (HHSN272201700059C).

Battling COVID-19 with Enovid Nitric Oxide Nasal Spray (NONS)

https://www.israelpharm.com/blog/enovid-nitric-oxide-nasal-spray/

This is where I bought the nasal spray, $45.00 each, free shipping,very fast delivery
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https://nocamels.com/2021/07/sanotize-covid-nasal-spray-israeli-pharmacies/

SaNOtize Rolls Out Anti-COVID Nasal Spray In Israel, Bahrain
By NoCamels Team July 15, 2021 5 minutes

Dr. Gilly Regev, co-founder of SaNOtize. Courtesy

Science TechnologyDr. Gilly Regev, co-founder of SaNOtize. Courtesy.
SaNOtize, the company behind an antiviral nasal spray for use against COVID-19, has begun selling its product in Israel and Bahrain, officially rolling out the Enovid, the company’s Nitric Oxide Nasal Spray (NONS). According to Dr. Gilly Regev, the Israeli-Canadian scientist who co-founded SaNotize, the company is also finalizing an agreement to sell the product in India in partnership with a local pharmaceutical company.
Enovid will go on sale at Israeli pharmacies for NIS 139 ($42), a price point she says the company is looking to bring down.

Dr. Regev tells NoCamels during a phone interview that the spray solution has proved effective against SARS-CoV-2, the virus that causes COVID-19, and its variants Alpha, Beta, Gamma, in lab tests conducted at Utah State University’s Antiviral Research Institute. The center is finalizing its testing against the Delta variant (first detected in India last year and also known as B.1.617.2), and Dr. Regev says she expects the same results.

“Our solution can kill the virus within 2 minutes,” she says, explaining that during lab tests, the spray stopped the coronavirus in its tracks within that time frame.

The spray is especially effective at suppressing viruses, she tells NoCamels, including influenza, rhinovirus, and others.

The Vancouver-based SaNOtize developed Enovid as a patented platform technology that allows for the topical delivery of nitric oxide. A naturally occurring nanomolecule with the formula NO (hence the name), it has proven anti-microbial properties that have been used to treat a variety of bacterial, fungal, and viral diseases.

The spray releases a small dose of nitric oxide and is designed to kill viruses in the upper airways. This prevents them from incubating and spreading to the lungs by providing a physical and chemical barrier.

Earlier this year, Enovid was granted an emergency use authorization as a medical device by Israel’s Ministry of Health and began a local production line. It has been approved for people 12 years of age and older.

Enovid is SaNOtize’s Nitric Oxide Nasal Spray (NONS) that protects from viruses and was shown to reduce SARS-CoV-2 viral load in a Phase II trial. Photo via Dr. Gilly Regev on LinkedIn.

SEE ALSO: Israeli Pharma Firm Says Nasal Spray Found Highly Effective Against COVID-19, Variants

“We are thrilled to have Enovid available in pharmacies in Israel and we are moving as quickly and diligently as possible through regulatory approval processes elsewhere in the world to make NONS available to the wider public,” said Dr. Chris Miller, SaNOtize co-founder and chief science officer, in a statement. “NONS was shown to reduce viral load, which decreases a person’s viral transmission, regardless of variant.”

The company completed a Phase II trial in Canada for COVID-19 and its variants and recently received approval from Health Canada to proceed with the enrollment of volunteers for Phase III trials. The approval for Phase III was granted for both prevention and early treatment separately, and SaNOtize plans to start with the prevention trial first.

The Health Canada approval follows results of a successful Phase IIb clinical trial in the UK by SaNOtize, Ashford and St Peter’s Hospitals NHS Foundation Trust in Surrey, and Berkshire and Surrey Pathology Services. The findings showed that SaNOtize’s Nitric Oxide Nasal Spray (NONS) was a safe and effective antiviral treatment that could prevent the transmission of COVID-19, shorten its course, and reduce the severity of symptoms and damage in those already infected.

The randomized, double-blind, placebo-controlled Phase II trial evaluated 79 confirmed cases of COVID-19, and showed that early treatment for COVID-19 with SaNOtize “succeeded in significantly reducing the level of SARS-CoV-2, including in patients with high viral loads,” the company said in March.

The study concluded that NONS accelerated clearance of SARS-CoV-2 by a factor of 16-fold versus the placebo. There were also no adverse health events recorded in the UK trial, or in over 7,000 self-administered treatments given in the Canadian clinical trials, SaNOtize indicated.

The results of the UK study are set to be published by the Journal of Infection, a monthly peer-reviewed medical journal in the field of infectious disease, covering microbiology, epidemiology, and clinical practice.

Dr. Regev tells NoCamels that SaNOtize’s solution “is based on strong scientific data” and that it’s “the only nasal spray company that has pursued clinical trials. This is what differentiates us from the rest.”

She indicates that the company is moving ahead with trial sites across the world to collect data on an even wider scale. The next trial will likely test how effective the solution is for helping to reduce symptoms.

In Israel, the company is in talks with the Ministry of Health to see if it will allow for the solution to be given to people who’d been exposed to a confirmed patient, she tells NoCamels.

Separately, SaNOtize also announced the appointments of Dan Suesskind, formerly the chief financial officer at Teva Pharmaceutical Industries, and Elaine Campbell, former president of AstraZeneca Canada, to its Board of Directors.

“As SaNOtize begins the next phase in its evolution, we are fortunate to welcome such experienced and respected leaders in the global pharmaceutical industry to our board,” said Dr. Regev in the statement. “Their expertise in expanding multinational pharmaceutical organizations will be invaluable.”

SaNOtize also indicated that it was in the process of regulatory submissions in several other countries including India, Brazil, and Mexico — states with some of the worst COVID-19 death rates.

“This will be affordable and can be used for prevention, to protect from any respiratory viral infection,” Dr. Regev told the Times of Israel in March, adding that the spray could help save lives in countries where access to the coronavirus vaccines is limited.

SEE ALSO: Israeli COVID-19 Vaccine Developer Inks Deal To Complete Trials, Commercialize Jab

Currently, scientists and researchers across the globe are closely watching surges of infections with the COVID-19 Delta variant, a more easily transmitted strain caused by mutations on the spike protein. It is the dominant strain in the US, the UK, and Israel, where restrictions such as mask-wearing indoors and distancing were reimposed in recent weeks as the country monitors the upward trend of infections (even as severe cases remain relatively low).

The Israeli Ministry of Health announced last week that the Delta variant was found to be more resistant to the vaccine. According to a recent analysis by the ministry, the Pfizer vaccine was considered 64 percent effective at preventing symptomatic and asymptomatic disease and also 93 percent effective at preventing hospitalization after infection, and death.
SaNOtize solutions

SaNOtize also developed a number of nitric oxide-based therapies to treat a variety of bacterial, fungal, and viral diseases.

It was previously granted US and EU patents on its Nitric Oxide Releasing Solution (NORS) and is testing ready-to-use applications delivered through gargle solutions, nasal spray, and nasal lavage. Separate trials have shown that the solution was effective in lab conditions against viruses such as influenza A, hCoV-OC43 and H1N1 (swine flu), the company has said.

Dr. Regev told NoCamels last year that the company’s solutions are also undergoing two separate clinical trials, one for fighting nail fungi and a second for chronic sinusitis.

“Both conditions currently don’t have treatment,” she pointed out on the sidelines of the annual OurCrowd summit last February. OurCrowd is an investor in SaNOtize.

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