Periodic Reporting for period 2 - MULTI-APP (Multivalent Molecular Systems for Innovative Applications) Reporting period: 2017-01-01 to 2018-12-31 Summary of the context and overall objectives of the project This network brings together the major academic research groups in Europe dealing with the fundamentals and applications of multivalency and cooperativity. The network is complemented by industrial partners that contribute to the training programme. The main objective of this consortium is to raise a new generation of researchers able to develop complex chemical systems that harness cooperativity for enhanced functional properties.Multivalency is one of Nature’s governing principles for achieving strong and selective biomolecular recognition. Many biological processes rely on the cooperative effects associated with the occurrence of multivalent interactions. Consequently, there is an enormous interest in the development of chemical multivalent systems that display similar features for innovative applications in fields as various as diagnostics, drug discovery, materials science and nanotechnology. In order for Europe to be at the front wave of this development, it needs to invest now in young researchers that understand how cooperativity works in multivalent systems, that are experts in preparing and characterising a wide variety of multivalent systems, and that are acquainted with the fundamentals, challenges and also the limitations of different applications.The central theme of multivalency and cooperativity is used to connect partners from academia and industry with a common interest in understanding how multivalency works, but for very different scopes and using very different approaches. This network is thus uniquely positioned to train the next generation of European researchers in all multidisciplinary aspects related to multivalency. A broad training programme has been developed that comprises top-level individual research projects, both general and specific network-wide dedicated courses, secondments, personalized scientific training and a broad package of complementary skill training. During the project, various industrial partners have contributed in the form of training, technical contributions, and perspectives on the commercialisation of multivalent systems. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The research part of the program is divided in three work packages. The first deals with a fundamental study of the origin of cooperativity in chemical model systems. A series of compounds have been synthesized and currently the interaction strength with a series of mono- and multidentate guests is being determined through tritration experiments. Theoretical models have been developed to quantify cooperativity in synthetic model systems. The second work package is dedicated to the application of multivalent dendrimers and polymers in bio-applications. A series of dendritic architectures of different valency have been synthesized and the interaction with the LOX-1 protein, a receptor involved in inflammatory processes, has been investigated using SPR. In a different project, polyglycerol-based tripodal scaffold molecules have been functionalized with sialic acid residues for influenza virus inhibition. In the third project, the dynamics of self-assembled polymers is exploited for the design of adaptive materials. Synthetic strategies have been developed to functionalize self-assembling disc-shaped molecules with peptide sequences involved in multivalent binding to protein targets. The final research package involves the study of multivalent systems for nanotechnology and materials. The interaction between nanoparticles and carbohydrates has been studied by means of fluorescent displacement and NMR diffusion experiments. In a second project a new method has been developed to modify plastic surfaces for the detection of multivalent biotargets. The interaction between a light-responsive hydrogel and cyclodextrin vesicles was studied and a reversible UV/vis responsive sol-gel transition was observed. In the final project, chemical reactivity has been studied in vesicles, which are transiently stabilized through multivalent interactions with an effector molecule. Promising initial results have been obtained that correlate the formation of reaction products to the stability of the nanoreactor. Finally, a collaborative project was dedicated to the development of light-responsive aggregates between nanoparticles and vesicles.During the duration of the project five network meetings and one final network symposium have been organized to provide the ESRs with extensive training dealing with all aspects of multivalency in a chemical and biological contact . The network meetings were in all cases organized around a specific theme related to multivalency and in the majority of cases organized in conjunction with a scientific congress/workshop/school open to a larger audience. One hand this allowed the ESRs to discuss their progress with the network partners, but also to connect to the larger scientific community. Two technical workshops were organized in which external experts taught on the Characterization of multivalent systems and Advanced analytical chemistry and data analysis, respectively. Two additional workshops were organized dedicated to the Exploitation of Research Results/Knowledge Transfer and Career development, respectively.The results have so far led to 7 publications in high-profile scientific journals with a significant number of additional manuscripts being submitted or being prepared for publication. Several of these publications are the result of collaborative projects originated and developed within the context of the network. In addition, results have been communicated by the ESRs on numerous occasions at (inter)national workshops and conferences by means of poster and/or oral presentations. Dissemination activities included, but were not limited to, participation of the ESRs in the European Researchers’ Night, local chemistry fairs and interviews with broadcasting stations. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The network has resulted in the successful training of 9 ESRs, all of which have obtained (or a close to obtaining) a doctorate degree. The network activities have prepared the ESRs optimally for research jobs in academia and industry on a research topic that addresses key societial issues. The intensive and broad training activities, together with secondments, permitted the ESRs to obtain a unique expertise with different chemical multivalent systems, the fundamental aspects of multivalency and their applications in drug delivery, sensing, materials and catalysis. High quality research has been developed by the ESRs as demonstrated by the publications in high-impact scientific journals. The results have been presented to the international scientific community at numerous meetings through oral communications and poster presentations. The network has sparked interactions between leading research groups in Europe on the theme of multivalency leading to scientific collaborations that will extend beyond the formal end of this network.