RELEASE: New Data Points to Spike Protein Interactions with Estrogen Receptors (1)

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RELEASE: New Data Points to Spike Protein Interactions with Estrogen Receptors (1)

(Information sent by the signatory company)

Dompé: New Published Data Points to Spike Protein Interactions with Estrogen Receptors as a Cause of Coagulopathy in COVID-19 Patients, Pointing to Gender Effects and a Pathway to Improved Vaccines

- A team of US and European researchers has published in Science Advances new findings showing how the SARS-CoV-2 Spike (S) protein interacts with human estrogen receptor alpha (ERα) in lung tissue

- Data published as preprint in bioRxiv reveal that the interaction of SARS-CoV-2 Spike (S) proteins with ERα may increase procoagulant activity of endothelial cells, increasing the risk of thrombosis and shedding new light on pathogenic mechanisms underlying SARS-CoV-2 infection and their specific differences by sex.

- Other data from the same research groups reveal the mechanism underlying some rare coagulopathies associated with vaccines, which can be prevented with small changes in the Spike sequence used to produce currently available vaccines.

MILAN and SAN MATEO, California, Dec. 1, 2022 /PRNewswire/ -- Dompé farmaceutici has announced new data revealing a new role for the interaction of the SARS-CoV-2 Spike (S) protein with Estrogen Receptor Alpha (ERα) that can cause the severe coagulopathy seen in patients with COVID-19 and in a minority of subjects receiving the SARS-CoV-2 vaccine. The data published today in Science Advances[1] is the result of a collaboration between researchers from Dompé farmaceutici, the National Institute on Drug Abuse, part of the US National Institutes of Health, Johns Hopkins University, the Institute Scripps, Stanford Medical School, and the University of L'Aquila, in Italy.

The SARS-CoV-2 virus is known to cause severe vasculopathy, which can, in turn, lead to fatal thrombosis. The team's findings are consistent with the sex-specific differences in thrombosis seen in hospitalized patients with COVID-19, and in a minority of subjects who received the SARS-CoV-2 vaccine, as reported earlier this year. year in the American Journal of Cardiology[2] by an unrelated team.

The initial finding that led to the study arose from the results of the Exscalate4CoV [3] (E4C) project, a group made up of 30 public and private institutions from seven countries and funded by the European Commission under its Horizon 2020 Framework Program [4 ], whose objective is to fight the coronavirus with the latest European supercomputing resources and experimental facilities. The project harnessed the computing power of Exscalate, Dompé's supercomputing platform that exploits a database of 500 billion molecules to find those capable of attacking clinically relevant coronavirus variants. Processing more than 3 million molecules per second, Exscalate is currently the most powerful intelligent drug design platform running on Leonardo[5], the world's fourth most powerful supercomputer. This processing power allowed the E4C researchers to rapidly select and retarget a generic molecule (raloxifene) of known efficacy and tolerability as an estrogen modulator for the treatment of osteoporosis. Using the Exscalate platform to identify Spike protein binding partners beyond the canonical ACE2 receptor, the researchers identified prominent interactions between two human estrogen receptors (ERα, ERβ) and the SARS-CoV-2 Spike protein. Following an unbiased primary screen to profile the binding of the full-length Spike protein to more than 9,000 other human proteins, the researchers found a consistent interaction with human estrogen receptor alpha (ERα). In addition, high levels of ERα were measured in the damaged lungs of infected hamsters, as well as in postmortem human lung samples. The researchers suggest that, given the role of ERα in the coagulation cascade, protein S could increase the procoagulant activity of endothelial cells, leading to an increased risk of thrombosis.

As circulating estrogens play a protective role in regulating the immune response to infection, it is possible that modulation of ER signaling in SARS-CoV-2-infected lung tissue may serve to stimulate the proinflammatory signals that drive to hypertrophy, vasoconstriction and obstruction of vessels. This concept has been validated through another set of experimental findings, reported in a pre-print[6] and submitted to a peer-reviewed publication, demonstrating that the interaction between the Spike protein and the ERα leads to increased tissue factor (TF) and general procoagulant activity in a human endothelial cell line, a result that is further confirmed by overexpressing protein S in mice. These results are consistent with the investigators' demonstration that deletion of the appropriate point mutations in the Spike sequence abolished ERα binding and its effects without compromising its immunogenicity and pointing to a way to mitigate the rare side effects seen with the currently available vaccines.

"Supercomputing has already demonstrated its ability to find answers to questions that we could not answer just a few years ago," said Roberto Viola, director general of the General Directorate of Communications, Content and Technology Networks (DG CONNECT) of the European Commission, which last week inaugurated the Leonardo supercomputer in Bologna, Italy. "And it will increasingly help us find solutions in all sorts of fields: from climate change with extreme weather forecasts and urban planning to understanding the human brain and body. Medicine is the field where supercomputing is already bearing concrete fruit. I am very proud of the support that the European Commission has given to the Exscalate4Cov consortium to discover promising leads to fight COVID-19 more effectively."

"Finally, the global evidence provides a strong justification for some previously published[7] results obtained by our team," explained Marcello Allegretti, scientific director of Dompé farmaceutici, adding: "Namely, the beneficial role of modulators of estrogen receptors, especially raloxifene, in preventing some of the side effects of infection and support the use of raloxifene for both therapy and vaccine side effects."

About Dompe

Dompé is a fast-growing private international biopharmaceutical company founded in Milan, Italy, with a 130-year legacy of medical innovation. The company's RD is based on EXSCALATE, an internally developed framework-based virtual screening platform that leverages one of the world's most powerful supercomputing and artificial intelligence platforms. Today, Dompé has more than 800 employees worldwide and maintains a US business operations center 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 be consistent 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 indeterminacy in relation to its research and development activities and the necessary verifications that must be carried out by regulatory bodies. Therefore, as of today, Dompé cannot guarantee that the expected results are consistent with the information provided.

1. Science Advances - The SARS-CoV-2 spike protein binds and modulates estrogen receptors - eadd4150 (2022) November 30, 2022 - Wilcox et al. Sex Differences in Thrombosis and Mortality in Patients Hospitalized for COVID-19, Am J Cardiol. May 1, 2022; 170: 112–117, The Exscalate4Cov consortium (, supported by the EU's Horizon 2020 program for research and innovation, was coordinated by Dompé farmaceutici, and comprised of 18 member institutions from seven European countries: Politecnico di Milano (Dept. of Electronics, Information and Bioengineering), Consorzio Interuniversitario CINECA (Supercomputing Innovation and Applications), Università degli Studi di Milano (Department of Pharmaceutical Sciences), International Institute of Molecular and Cell Biology in Warsaw (Warsaw, Poland), KU Leuven, Elettra Sincrotrone Trieste, Fraunhofer Institute for Molecular Biology and Applied Ecology, BSC Barcelona Supercomputing Center, Forschungszentrum Jülich, Università Federico II di Napoli, Università degli Studi di Cagliari, SIB Swiss Institute of Bioinformatics, KTH Royal Institute of Technology (Department of Applied Physics), Associazione Big Data, National Institute of Nuclear Physics (INFN), National Institute for Nuclear Physics alattie infettive Lazzaro Spallanzani and Chelonia Applied Science. The following participated in the E4C League: ENI, SAS, Alfasigma, CFEL Center for Free-Electron Laser Science, MMV Medicines for Malaria Ventures, Esteve Pharmaceutical, University of Basel Biozentrum, University of Basel Innovation Office, University of Basel Department of Pharmaceutical Sciences, D -wave, Pierre fabre, Greenpharma, University of Sheffield - Sheffield Institute for Translational Neuroscience - SITraN, Dassault Systemes- Biovia, Institute of Food Science Research, CECAM Center Européen de Calcul Atomique et Moleculaire, Nanome, Esteco, IT4Innovation, Università degli Studi della Tuscia, Sofia University "St. Kl. Ohridski", Faculty of Physics, Cochin Institute.4. EXaSCale smArt pLatform Against paThogEns for Corona Virus / Grant agreement ID: 101003551 Barbieri et al. - Relevance of the viral Spike protein/cellular Estrogen Receptor-a interaction for endothelial-based coagulopathy induced by SARS-CoV-2; BioRxiv 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.

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