The Exscalate4CoV project identified Raloxifene as a possible treatment against the COVID-19 disease. Developed in the late 1990s to prevent and treat osteoporosis, the Raloxifene molecule is widely used and safe for patients. The research work performed by the project so far indicated that this molecule could be a suitable option for treating patients in the early stages of COVID-19 and in countering replication of the Sars-Cov2 virus in cells.
As the molecule is a marketed drug, the European Medicines Agency (EMA) has already approved its use for treating osteoporosis. The consortium is discussing with EMA the fastest path to clinical trials in humans for COVID-19 disease. The Exscalate4CoV project coordinator Dompé has filed a global patent with the two project laboratories, Fraunhofer IME in Germany and KU Leuven in Belgium, on 6 May 2020, addressing the molecule as an inhibitor to SARS-CoV-2. After these steps, and once confirmed by the clinical tests, the drug might be used on a wider scale.
Exscalate4CoV builds on two distinct but closely interconnected streams of activities: one relies on HPC capacities, in combination with AI, bioinformatic and chemoinformatic technologies, and the other combines the available knowledge with a genomic, biochemical and biological approach in order to identify molecules for a potential drug.
The first step is to obtain the structure of the virus. Three partners – the International Institute of Molecular and Cell Biology (IIMCB), Elettra Sincrotrone Trieste and the Swiss Institute of Bioinformatics (SIB) – crystallise the virus’ protein and provide its 3D structure. E4C has identified 25 different protein models that constantly evolve, with various mutations received weekly, each translated into a digital form to be used in the following step.
Next are the HPC docking operations (in-silico tests). Exscalate4CoV possesses a chemical library of over 10,000 drugs and 500 billion molecules, with pharma companies submitting new molecules to the database since March. With a computing capacity of more than 120 million billion operations per second, four supercomputers are used to match the digital signature of coronavirus proteins against molecules from the chemical library. The project has already virtually tested 400 000 molecules using its supercomputers. 7 000 molecules were preselected and further tested “in vitro”. The results obtained from Exscalate4CoV are protected by Intellectual Property that promotes universal access. All scientific data produced by the consortium will be released in open domain.
Three of Europe’s most powerful supercomputing centres – based in Bologna, Barcelona and Jülich – provide the project’s HPC capacities, and Italian energy company Eni offered its HPC facilities in early April, enabling a joint supercomputing power of over 90 Petaflops. Originally created to identify molecules during the Zika virus crisis, E4C uses the EXSCALATE (EXaSCale smArt pLatform Against paThogEns) platform, currently the most powerful (and cost-efficient) supercomputing platform in the world. It uses both AI and HPC technologies to compliment the traditional “trial and error” clinical approach in advanced computer-aided drug design in Europe. EXSCALATE drives a fast virtual identification of known drugs or commercial candidate molecules to be further experimentally characterised.
Exscalate4CoV is also setting up a dedicated data space called MEDIATE (MolEcular DockIng AT homE), which will make protein models and drug libraries available to Europe’s computational community. These elements will be mediated, and any additional proposed compounds will be acquired and tested during the project’s second phase. The project will also publish all of its data (positive and negative results) on the EU COVID-19 research data platform, which was put in place in April 2020.
In the project’s second phase, Exscalate4CoV partners will focus on improving the EXSCALATE platform: improving the artificial intelligence (AI) and modelling tools of the platform, and, using it for operating a wider search for a creating a completely new antiviral drug against the corona or similar viruses. With all of the pharmaceutical data received, the process endured and the experience gained, the platform may hold the key to dealing with future outbreaks.
Receiving €3 million of EU funding over a period of 18 months, Exscalate4CoV is one of the 18 projects that began operating in March 2020, following the Commission’s emergency call to fund research for the detection, treatment and prevention of COVID-19.
Coordinated by Italian pharma company Dompé, Exscalate4CoV is a consortium of 18 partners based across seven European countries (Belgium, Germany, Italy, Poland, Spain, Sweden and Switzerland). The consortium includes the supercomputing centres CINECA in Italy, BSC in Spain, and FZJ in Germany, and several large institutions and research centres situated across Europe: the Polytechnic University of Milan (POLIMI), the University of Milan (UNIMI), KU Leuven, the International Institute of Molecular and Cell Biology (IIMCB), Elettra Sincrotrone Trieste, Fraunhofer IME, Lazzaro Spallanzani National Institute for Infectious Diseases (INMI), the University of Naples (UNINA), the University of Cagliari (UNICA), the Swiss Institute of Bioinformatics (SIB), KTH Royal Institute of Technology, Associazione BigData, the National Institute for Nuclear Physics (INFN), and Chelonia Applied Science.