SARS-CoV-2 S protein

Researchers have found that the genes of the mitochondria, the energy producers of our cells, can be negatively impacted by the virus, leading to dysfunction in multiple organs beyond the lungs. These findings suggest new approaches for treating COVID-19. Since the beginning of the COVID-19 pandemic caused by the SARS-CoV-2 virus, researchers have been trying to determine why this virus creates such negative long-term effects compared with most coronaviruses. Now, a multi-institutional consortium of researchers led by a team at Children's Hospital of Philadelphia (CHOP) and the COVID-19 International Research Team (COV-IRT) has found that the genes of the mitochondria, the energy producers of our cells, can be negatively impacted by the virus, leading to dysfunction in multiple organs beyond the lungs. These findings, published online today by the journal Science Translational Medicine, suggest new approaches for treating COVID-19. Mitochondria are found in every cell in our bodies. The genes responsible for generating mitochondria are dispersed across both the nuclear DNA located in the nucleus of our cells and the mitochondrial DNA (mtDNA) located within each mitochondrion. Prior studies have shown that SARS-CoV-2 proteins can bind to mitochondrial proteins in host cells, potentially leading to mitochondrial dysfunction. To understand how SARS-CoV-2 impacts mitochondria, researchers from the Center for Mitochondrial and Epigenomic Medicine (CMEM) at CHOP along with their COV-IRT colleagues wanted to analyze mitochondrial gene expression to detect differences caused by the virus. To do this, they analyzed a combination of nasopharyngeal and autopsy tissues from affected patients and animal models. "The tissue samples from human patients allowed us to look at how mitochondrial gene expression was affected at the onset and end of disease progression, while animal models allowed us to fill in the blanks and look at the progression of gene expression differences over time," said the study's first author Joseph Guarnieri, PhD, a postdoctoral research fellow with the CMEM at CHOP. The study found that in autopsy tissue, mitochondrial gene expression had recovered in the lungs, but mitochondrial function remained suppressed in the heart as well as the kidneys and liver. When studying animal models and measuring the time when the viral load was at its peak in the lungs, mitochondrial gene expression was suppressed in the cerebellum even though no SARS-CoV-2 was observed in the brain. Additional animal models revealed that during the mid-phase of SARS-CoV-2 infection, mitochondrial function in the lungs was beginning to recover. Taken together, these results reveal that host cells respond to initial infection in a way that involves the lungs, but over time, mitochondrial function in the lungs is restored, while in other organs, particularly the heart, mitochondrial function remains impaired. "This study provides us with strong evidence that we need to stop looking at COVID-19 as strictly an upper respiratory disease and start viewing it as a systemic disorder that impacts multiple organs," said co-senior author Douglas C. Wallace, PhD, director of the CMEM at CHOP. "The continued dysfunction we observed in organs other than the lungs suggests that mitochondrial dysfunction could be causing long-term damage to the internal organs of these patients." While future studies using this data will study how systemic immune and inflammatory responses may be responsible for more severe disease in some patients, the research team did find a potential therapeutic target in microRNA 2392 (miR-2392), which was shown to regulate mitochondrial function in human tissue samples used in this study. "This microRNA was upregulated in the blood of patients infected by SARS-CoV-2, which is not something we normally would expect to see," said co-senior author Afshin Beheshti, PhD, a biostatistician, a visiting researcher at The Broad Institute, and founder and President of COV-IRT. "Neutralizing this microRNA might be able to impede the replication of the virus, providing an additional therapeutic option for patients who are at risk for more serious complications related to the disease." Earlier this year, The Gates Foundation provided funding to Dr. Wallace and CMEM for research into how mtDNA variation among world populations might affect mitochondrial function and thus individual sensitivity to SARS-CoV-2. According to Wallace, the demonstration that SARS-CoV-2 markedly affects mitochondrial function supports the hypothesis that individual differences in mitochondrial function could be a factor in individual severity of COVID-19. This work was also supported by the Division of Intramural Research, NIAID, NIH and, in part, by the Bill & Melinda Gates Foundation grant INV-046722.

Unprecedented comprehension of the interaction between Spike and the Human Estrogen Receptor Alfa provides insights for a new generation of anti SARS-CoV-2 and pan-Coronavirus vaccines Italian and US researchers have revealed how the SARS-CoV-2 Spike protein interacts with human Estrogen Receptor-α (ERα) leading to severe coagulopathy observed in COVID-19 patients. The new data - published in Nature’s Signal Transduction and Targeted Therapy - shows that point mutations in the sequence of SARS-CoV-2 Spike (S)-protein eliminate its pro-coagulation effect without compromising immunogenicity. The findings provide actionable insights for designing vaccines lacking of estrogen-receptor mediated side effects for all coronavirus strains and other viral infections. MILAN & SAN MATEO, Calif.--(BUSINESS WIRE)-- Dompé farmaceutici announced today new peer-reviewed data demonstrating that small changes in the SARS-CoV-2 Spike (S)-protein sequence can eliminate its effect in inducing coagulation1. The tendency for the Spike protein to stimulate inflammatory and coagulation has been implicated in coagulopathy observed in the lungs, heart and kidneys of COVID-19 patients with a similar and extremely rare effects observed in a minority of patients who received COVID-19 vaccines. This press release features multimedia. View the full release here: Framework Dompé farmaceutici Biotech production (Photo: Business Wire) Data stemmed from the EXSCALATE supercomputing calculation predicted a potential function of Spike (S) as a co-factor for human ERα nuclear signalling. This interaction is mediated by a nuclear receptor co-regulator (NRC) LXD-like motif present on the viral protein S2 subunit, and the activation function 2 (AF-2) region on ERα2. This work builds on other recent studies3,4 showing that coagulopathy is clearly associated with the interaction of the SARS-CoV-2 Spike (S) protein with the human Erα. While circulating estrogens play a protective role by regulating the immune response to infection, modulation of ERα signalling in SARS-CoV-2-infected lung tissue stimulates proinflammatory signals leading to hypertrophy, vasoconstriction, and vessel obstruction. In the new article the scientists of the italo-american collaboration (encompassing Centro Cardiologico Monzino in Italy and the National Institute on Drug Abuse and the Johns Hopkins School of Medicine in the US) demonstrated that the interaction between the Spike protein and ERα leads to an increase in tissue factor (TF) and the overall pro-coagulation activity in two human endothelial cell lines. The results were further validated by overexpressing S-protein in mice. This pro-coagulative function of Spike in vitro and in vivo, was abolished or strongly reduced by the variants of the Spike proteins carrying mutations in the interaction domain with ERα (as predicted by EXSCALATE). “The value and benefits of vaccines in countering the COVID-19 pandemic remain unquestionable and overwhelming compared to the risks associated with infection from SARS-CoV-2” underscores Maurizio Pesce, a research Group Leader at the Monzino Cardiology Center in Milan, Italy, and initiator of the study in 2021 together with the leading Silvia Barbieri, another research Group Leader at Monzino, “We hope that our findings will be considered in the development of the next generation of vaccines reducing the residual side effects and risks. Our data also unravel a new function of the viral protein in direct regulation of thrombosis associated factors. This has general implications not only for COVID-19, but for other viral infections altering the coagulation pro patients”. “This continuing research is critical to understand the pathogenetic mechanisms associated with SARS-CoV2 infection and causal mechanisms of some rare COVID-19 vaccine side effects,” says Dompé farmaceutici Chief Scientific Officer Marcello Allegretti “Ongoing expanding data is revealing a well-conserved region with the same characteristics of the LXD-like motif present on the viral protein S2 subunit, also in other Coronaviruses. This evidence could open new scenarios in ‘pan-Coronavirus’ vaccination. We are excited to identify a path toward further refinement strategies to enable even more powerful benefits through future vaccination and booster initiatives”. ____________________________________________________________________________________ About Dompé Dompé is a private, rapidly scaling international biopharmaceutical company founded in Milan, Italy, with a 130-year legacy of medical innovation. The R&D department of the company is anchored by EXSCALATE, a structure-based virtual screening platform developed in-house that leverages one of the most powerful supercomputing and artificial intelligence platforms in the world. Today, Dompé employs more than 800 employees worldwide and maintains a US commercial operations hub in the San Francisco Bay Area as well as an R&D presence in Boston. Forward Looking Statements This press release refers to certain information that may not coincide with expected future results. Dompé firmly believes in the soundness and reasonableness of the concepts expressed. However, some of the information is subject to a certain degree of indetermination in relation to its research and development activities and the necessary verifications to be performed by regulatory bodies. Therefore, as of today, Dompé cannot guarantee that the expected results will be consistent with the information provided above. 1. SS Barbieri et al. Relevance of the viral Spike protein/cellular Estrogen Receptor-α interaction for endothelial-based coagulopathy induced by SARS-CoV-2 - Signal Transduction and Targeted Therapy - 2. Allegretti, M. et al. Repurposing the estrogen receptor modulator raloxifene to treat SARS-CoV-2 370 infection. Cell Death Differ. 29, 156-166 (2022). 371 - 3. Wilcox et al. Sex Differences in Thrombosis and Mortality in Patients Hospitalized for COVID-19, Am J Cardiol. 2022 May 1; 170: 112–117 - 4. Science Advances - The SARS-CoV-2 spike protein binds and modulates estrogen receptors - eadd4150 (2022) 30 November 2022 -

PatSnap Synapse, a novel, AI Powered Drug Competitive Intelligence database. Access to drugs, clinical trials, patents, literature and news in one search Nykode Therapeutics, a biopharmaceutical company based in Oslo, Norway, has announced positive final results from its Phase 2 clinical trial evaluating the safety and efficacy of VB10.16 in combination with the PD-L1 inhibitor, atezolizumab, for the treatment of advanced or recurrent, non-resectable HPV16-positive cervical cancer. The trial involved 52 patients with advanced cervical cancer who had previously received chemotherapy. The study aimed to evaluate the safety and efficacy of VB10.16, a therapeutic vaccine that works by stimulating the immune system to target cancer cells, in combination with atezolizumab, a checkpoint inhibitor that blocks PD-L1 to enhance immune responses against cancer. The results showed that the combination of VB10.16 and atezolizumab was well-tolerated and demonstrated promising clinical activity in patients with advanced cervical cancer. The overall response rate was 40% and DCR 80% with a median progression free survival of 16.9 months and median overall survival more than 25 months (not reached). Nykode Therapeutics was founded in 2007 and is focused on developing treatments for respiratory diseases, neoplasms, and infectious diseases. The company's drug development technologies include DNA vaccines, therapeutic vaccines, prophylactic vaccines, and more. Nykode Therapeutics has also been actively developing treatments for SARS-CoV-2 S protein, a frequent target for its drug development efforts. VB10.16 is a DNA therapeutic vaccine for neoplasms and urogenital diseases, including uterine cervical cancer. It is a product of Nykode Therapeutics and modulates antigen-presenting cells to elicit an immune response against cancer cells. The highest phase of its clinical trials is Phase 2.