The ambition of the PIANOFORTE Partnership is to improve radiological protection of members of the public, patients, workers and environment in all exposure scenarios and provide solutions and recommendations for optimised protection in accordance with the Basic Safety Standards. Research projects focusing on identified research and innovation priorities will be selected through a serie of three competitive open calls. The input to define the research priorities will be based on the priorities defined in the Joint Road Map (JRM) developed during the H2020 CONCERT EJP but also on the results of ongoing H2020 projects and on the expectations expressed by other actions carried out in other European programmes, in particular the SAMIRA action plan. High priority will be dedicated to medical applications considering that 1) medical exposures are, by far, the largest artificial source of exposure of the European population and 2) the fight against cancer is a top priority of the present European Commission. In order to ensure an appropriate continuity in the research goals and methodologies, in line with the contents of the CONCERT JRM, two other priorities have been identified to further understand and reduce uncertainties associated with health risk estimates for exposure at low doses in order to consolidate regulations and improve practices and to further enhance a science-based European methodology for emergency management and long-term recovery. Once the research priorities defined, the open call system will promote excellence in science and widening participation through a process open to the whole radiation protection community. Beyond the research actions, the selected projects will be able to benefit from the system of sharing and mutualisation of infrastructures that will be implemented at the European level. This will be accompanied by education and training schemes for health workforce and young scientists to increase Europe’s research capacity in the field.

With progress in globalization, expansion of human populations into natural habitats, and aggravation of climate change comes an increased risk of viral outbreaks. As demonstrated by the COVID-19 pandemic, not being prepared for such events has devastating consequences on public health, society and the economy. EvaMobs will improve preparedness of the European Union (EU) for the next viral outbreak(s) of pandemic potential by developing a platform for the discovery, development, production and validation of evolvable and rapidly adaptable antivirals. These innovative medicines will be based on small human-derived proteins called monobodies (Mobs). As Mobs can be engineered to have high binding affinity for virtually any viral protein, this platform can be easily adapted to a broad range of viruses, including newly emerging viruses and viral variants. To demonstrate the capacity of this platform it will first be applied to four pathogenic viruses with epidemic and/or pandemic potential: Influenza A, SARS-CoV-2, respiratory syncytial virus, and Zika virus. Deep-learning and computational design tools will allow generation of tailor-made Mobs with cryo-EM elucidating the molecular details of their binding interaction. Simple bacterial expression of Mobs, the development of a semi-automated high-throughput screening platform for evaluation of the Mobs’ stability and target affinity and streamlined in vitro and in vivo preclinical validation, will allow rapid development and selection of stable and potently neutralizing candidates. The Mob with the best preclinical indicators will then be tested in a phase I clinical trial after implementing a stable formulation and GMP production. The optimized platform can then be adapted to other viruses. Therefore, EvaMobs provides an innovative, robust and flexible platform for antiviral biologics development as well as a diverse portfolio of validated drugs, strengthening the EU’s pandemic preparedness.

The inhibition of the enzyme butyrylcholinesterase (BChE) in human tissues by binding of compounds to its active site serine is important for the detoxification and scavenging of xenobiotics such as organophosphates (OP) as well as for the metabolism of pro-drugs and drugs such as the carbamate bambuterol and the phenothiazine ethopropazine. Despite of the importance of BChE, its kinetic reactions were investigated mostly as comparative studies on the related enzyme acetylcholinesterase (AChE), which has a vital function in cholinergic neurotransmission. Moreover, reactivators of inhibited BChE, as well as drugs for the treatment of neurodegenerative diseases were empirically synthesized before the BChE crystal structure was resolved. Due to specific structural requirements, its binding affinity, inhibition and reactivation rates have not been rigorously investigated. It is known from our recent analyses that reactivation rates are influenced by experimental design and reactivation assays need to account for side reactions – oximolysis, reversible inhibition, and adequate dilution in Ellman reaction in order to effectively quench the reactivation reaction. Therefore, this project utilizes known and new compounds to gain a better understanding of the mechanistic basis of cholinesterase family interactions and their limitations. The biochemical mechanism of enzyme interactions will be comprehensively studied on a molecular level with in silico, in vitro, and ex vivo methods. Kinetic constants of the studied interactions will be determined based on known kinetic models, while in need of unusual regression analysis new kinetic models will be developed. These comprehensive analyses will explain structural requirements for compounds interacting with BChE and gain a platform for synthesis of reactivators of phosphylated BChE and potentially active drugs in disorders that involve BChE inhibition. Many of the findings that should arise from this project will impact the mechanisms of hydrolytic catalysis, extending beyond the field of cholinesterases.