IKKγ

Over the past two years, scientists have studied the SARS-CoV-2 virus in great detail, laying the foundation for developing COVID-19 vaccines and antiviral treatments. Now, scientists have seen one of the virus's most critical interactions, which could help researchers develop more precise treatments. Over the past two years, scientists have studied the SARS-CoV-2 virus in great detail, laying the foundation for developing COVID-19 vaccines and antiviral treatments. Now, for the first time, scientists at the Department of Energy's SLAC National Accelerator Laboratory have seen one of the virus's most critical interactions, which could help researchers develop more precise treatments. The team caught the moment when a virus protein, called Mpro, cuts a protective protein, known as NEMO, in an infected person. Without NEMO, an immune system is slower to respond to increasing viral loads or new infections. Seeing how Mpro attacks NEMO at the molecular level could inspire new therapeutic approaches. To see how Mpro cuts NEMO, researchers funneled powerful X-rays from SLAC's Stanford Synchrotron Radiation Lightsource (SSRL) onto crystallized samples of the protein complex. The X-rays struck the protein samples, revealing what Mpro looks like when it dismantles NEMO's primary function of helping our immune system communicate. "We saw that the virus protein cuts through NEMO as easily as sharp scissors through thin paper," said co-senior author Soichi Wakatsuki, professor at SLAC and Stanford. "Imagine the bad things that happen when good proteins in our bodies start getting cut into pieces." The images from SSRL show the exact location of NEMO's cut and provide the first structure of SARS-CoV-2 Mpro bound to a human protein. "If you can block the sites where Mpro binds to NEMO, you can stop this cut from happening over and over," SSRL lead scientist and co-author Irimpan Mathews said. "Stopping Mpro could slow down how fast the virus takes over a body. Solving the crystal structure revealed Mpro's binding sites and was one of the first steps to stopping the protein." The research team from SLAC, DOE's Oak Ridge National Laboratory, and other institutions published their results today in Nature Communications. Protecting an immunity pathway NEMO is part of a human immune system known as the NF-κB pathway. You can think of NEMO and the NF-κB pathway as if they were a card reader and wiring on the outside of a locked building entrance door. If the wires to the card reader are cut, the door will not open, meaning a person (or an immune system activator, like NEMO) is stuck outside, unable to do whatever they came to do. The NF-κB pathway is a critical part of protective inflammatory responses. When NEMO is cut, our immune response can't be activated, resulting in various detrimental effects to our body. COVID-19 viral infections could be made worse if Mpro destroys NEMO, helping the virus evade our innate immune responses. Additionally, a separate study by researchers at institutions in Germany found that the loss of NEMO by the action of Mpro could lead to damage in certain brain cells, causing neurological symptoms observed in COVID-19 patients, the researchers said. One drug that is currently approved for emergency use targets Mpro proteins by providing an infected person with an Mpro inhibitor. This kind of inhibitor drug could be strengthened now that the location of NEMO's cut has been observed. "The crystal structures of NEMO and Mpro provide us with the targets to develop treatments that stop these cuts from happening," SLAC scientist and co-first author Mikhail Ali Hameedi said. "Although current antiviral drugs can target Mpro, seeing the molecular details of how Mpro attacks NEMO will help us develop new treatments in the future as Mpro mutates." Finding ways to improve antiviral inhibitors is especially important with SARS-CoV-2. Among the coronaviruses -- a group that includes the original SARS-CoV and MERS‐CoV viruses -- SARS-CoV-2's Mpro is the most effective at attaching to and cutting NEMO. SARS-CoV-2's Mpro grabs NEMO with a tighter grip than its counterparts in other coronaviruses and could be cutting hundreds of other critical proteins in human host cells, such as those associated with blood disorders, the researchers said. To predict how well Mpro binds to NEMO, researchers used the Summit supercomputer at the Oak Ridge Leadership Computing Facility. They combined molecular dynamics simulations with five machine learning models in a novel way and applied quantum chemistry, finding that Mpro likely has the highest binding affinity in SARS-CoV-2 compared to the other primary coronaviruses. In previous studies, these techniques helped scientists narrow down a list of potential antiviral inhibitor drugs. "With a set of computational approaches, we were able to predict the strongest binding spots between NEMO and Mpro," co-first author and ORNL scientist Erica Prates said. "We think that a high binding affinity at these hot spots helps explain the high fitness of the virus in humans." Moving forward, the biomedical industry could use the study to help build better inhibitor drugs and understand how other proteins could be affected by Mpro, Wakatsuki said. "NEMO is only the tip of the iceberg," he said. "We can now study what happens when many other proteins in the body are cleaved by Mpro during infection." This work was supported by the DOE's Office of Science, Office of Basic Energy Sciences and the Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences. Additional support came from the National Virtual Biotechnology Laboratory, a group of DOE national laboratories that is focused on responding to COVID-19 pandemic, with funding provided by the Coronavirus CARES Act. SSRL is an Office of Science user facility.

New York, NY, and Tel Aviv, ISRAEL, Aug. 19, 2022 (GLOBE NEWSWIRE) -- via NewMediaWire -- Todos Medical Ltd. (OTCQB: TOMDF), a comprehensive medical diagnostics and related solutions company, today announced that its majority-owned joint venture 3CL Pharma Ltd. reported the preprint in ResearchGate of results from the first 100-participant study from an IRB-waived market research study entitled “The Value of 3CL Protease Inhibitor Supplementation in Long Haul Syndrome Patients?” overseen by Dr. Dorit Arad in concert with Andrew A. Blumenthal, RN ADS. Participants in the study are primarily patients with Post-Acute Sequelae of COVID (PASC, or “Long COVID”) as well as participants with acute COVID infection. The results to date indicate the participants appear to experience benefit after supplementation with 3CL protease inhibitor immune support supplement Tollovid™. The publication preprint can be viewed at: . ABSTRACT In moderate to severe acute COVID-19 and Long Haul Syndrome (LHS), innate and adaptive immunological dysregulation is frequently observed and can persist for months, leading to a significant decline in clinical status and quality of life for many individuals. One hallmark of an over-exuberant immunological response is cytokine hyperactivity ('cytokine storm') that can lead to severe acute respiratory distress syndrome in certain patients. Reduced immunopathology and clinical resolution of the acute disease, on the other hand, appear to be associated with a powerful early innate antiviral response coupled with viral neutralization in such patients. The mechanisms by which the SARS-CoV-2 virus may subvert the host immune response are the subject of focused research in an effort to define virally-encoded factors that might be targeted for therapeutic intervention. One such target is the 3CL protease (3CLpro, Main protease, Mpro, Nsp5), sometimes referred to as the 'Achilles heel' of the SARS-CoV-2 virus. 3CLpro is essential to viral replication, and can also have direct, deleterious effects on the host's immune response, potentially via NEMO inactivation, thereby impacting the ability to resolve infections. Viral protease inhibitors have been used in several licensed oral medications and are well-validated therapeutic targets for the treatment of hepatitis C virus (HCV) and the human immunodeficiency virus (HIV). Indeed, pharmaceutical 3CLpro inhibitors are currently the most prescribed antiviral therapy for COVID-19. Here, through a series of 104 case study respondents in an IRB-waived market research self-reported questionnaire, we highlight emerging evidence concerning positive clinical and immunological impacts of supplementation with Tollovid, a natural, botanically-based immune cleanse/support dietary supplement with potent 3CL protease inhibitory activity in vitro, first reported here, in patients suffering from Acute COVID and LHS-related symptoms. To purchase Tollovid please visit Amazon or . About Tollovid™ and Tollovid Daily™ Tollovid and Tollovid Daily are oral dietary supplement products made from natural ingredients that help support and maintain healthy immune function and also have potent 3CL protease inhibition properties based upon in vitro functional assays that show strong inhibition of 3CL protease activity. Tollovid and Tollovid Daily bind to the active site of the 3CL protease. Tollovid has a 5-day dosing regimen, with 4 doses of 3 pills taken each day that provides maximum immune support. Tollovid Daily is a daily immune support product with a dosing regimen of twice daily. Preliminary data from an ongoing IRB-waived study of customers who used the products to assist with their COVID and Long COVID were recently announced. To purchase Tollovid please visit Amazon or . About Tollovir™ Tollovir is an oral 3CL protease inhibitor and anti-cytokine therapeutic candidate targeting the Nidovirus group of viruses that includes coronaviruses such as SARS-CoV-2, COVID-19, SARS-CoV-1, MERS and 229E. Tollovir is made from all natural ingredients that are qualified to ensure strong inhibition of the 3CL protease in vitro, as well as strong anti-cytokine activity. Tollovir has successfully completed a Phase 2 clinical trial in Israel for the treatment of patients hospitalized with COVID-19. Tollovir will be developed for the treatment of hospitalized COVID-19 (severe and critical), moderate COVID-19, Long COVID and, potentially, pediatric COVID-19. About Todos Medical Ltd. Founded in Rehovot, Israel with offices in New York City, Todos Medical Ltd. (OTCQB: TOMDF) engineers life-saving diagnostic solutions for the early detection of a variety of cancers. The Company's state-of-the-art and patented Todos Biochemical Infrared Analyses (TBIA) is a proprietary cancer-screening technology using peripheral blood analysis that examines cancer's influence on the immune system, looking for biochemical changes in blood mononuclear cells and plasma. Todos’ two internally developed cancer-screening tests, TMB-1 and TMB-2 have received a CE mark in Europe. Todos recently acquired U.S.-based medical diagnostics company Provista Diagnostics, Inc. to gain rights to its Alpharetta, Georgia-based CLIA/CAP certified lab currently performing PCR COVID testing, Long COVID Panel analyses, and Provista's proprietary commercial-stage Videssa® breast cancer blood test. More information on Provista is available at . Todos is also developing blood tests for the early detection of neurodegenerative disorders, such as Alzheimer's disease. The Lymphocyte Proliferation Test (LymPro Test™) is a diagnostic blood test that determines the ability of peripheral blood lymphocytes (PBLs) and monocytes to withstand an exogenous mitogenic stimulation that induces them to enter the cell cycle. It is believed that certain diseases, most notably Alzheimer's disease, are the result of compromised cellular machinery that leads to aberrant cell cycle re-entry by neurons, which then leads to apoptosis. LymPro is unique in the use of peripheral blood lymphocytes as a surrogate for neuronal cell function, suggesting a common relationship between PBLs and neurons in the brain. Todos formed the Israeli-based majority-owned joint venture 3CL Pharma, Ltd with NLC Pharma in March of 2022 to consolidate all of the intellectual property surrounding 3CL protease – based diagnostic testing and development of 3CL protease botanical and pharmaceutical inhibitors that target a fundamental reproductive mechanism of coronaviruses. 3CL Pharma, through Todos’ brand, has commercialized the 3CL protease inhibitor immune support dietary supplement Tollovid™ in the United States, is developing the dual mechanism 3CL protease inhibitor and anti-cytokine therapeutic drug candidate Tollovir™, while also developing the 3CL protease diagnostic TolloTest™. To purchase Tollovid please visit Amazon or . For more information, please visit . Forward-looking Statements Certain statements contained in this press release may constitute forward-looking statements. For example, forward-looking statements are used when discussing our expected clinical development programs and clinical trials. These forward-looking statements are based only on current expectations of management, and are subject to significant risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements, including the risks and uncertainties related to the progress, timing, cost, and results of clinical trials and product development programs; difficulties or delays in obtaining regulatory approval or patent protection for product candidates; competition from other biotechnology companies; and our ability to obtain additional funding required to conduct our research, development and commercialization activities. In addition, the following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; delays or obstacles in launching our clinical trials; changes in legislation; inability to timely develop and introduce new technologies, products and applications; lack of validation of our technology as we progress further and lack of acceptance of our methods by the scientific community; inability to retain or attract key employees whose knowledge is essential to the development of our products; unforeseen scientific difficulties that may develop with our process; greater cost of final product than anticipated; loss of market share and pressure on pricing resulting from the competition; and laboratory results that do not translate to equally good results in real settings, all of which could cause the actual results or performance to differ materially from those contemplated in such forward-looking statements. Except as otherwise required by law, Todos Medical does not undertake any obligation to publicly release any revisions to these forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. For a more detailed description of the risks and uncertainties affecting Todos Medical, please refer to its reports filed from time to time with the U.S. Securities and Exchange Commission. Todos Corporate Contact: Daniel Hirsch CFO Todos Medical 917-983-4229 x 104 Dan.h@todosmedical.com