Funded projects

Executive Summary
The sustainability of plastic materials implies attaining a renewable origin and recyclable nature. Unfortunately, both conditions are far from being fulfilled by the current industry. In the polyester sector, PET, one of the most common plastics, has a petrochemical origin. Happily, PEF is emerging as a biobased alternative to PET. Moreover, enzymatic biocatalysis can contribute to the industrial and environmental feasibility of bioplastics with next generation technologies for the synthesis and recycling of both building blocks and polymers.
Some of the most relevant enzymes are not optimally suited to oxidize or hydrolyze plastic compounds (since they naturally evolved to act on their natural counterparts). Therefore, protein engineering is mandatory to optimize them in terms of substrate specificity and operational conditions. In this process, rational engineering will be possible when supported by extensive computational simulations of the access, accommodation and reaction of target substrates at the active site of the selected enzymes. For these studies, advanced software simulating substrate binding by the enzymes and their engineered variants needs to be used. This will be combined with datasets of relevant enzymes and predictive models by regression simulation and machine learning.
FURENPOL combines the relevant actors to fulfil the main studies mentioned above in an interdisciplinary consortium including Research and Industrial representatives for both the Biotechnology and Plastic (synthesis and recycling) sectors. The former includes the CSIC coordinator (group of Biotechnology for Lignocellulosic Biomass at CIB) with large background in industrial enzymes, the Barcelona Supercomputing Center (group of Electronic and Atomic Protein Modeling) providing its supercomputational facilities, and the UAB (department of Chemical, Biological & Environmental Engineering, and Pilot-Plant) optimizing enzyme production and target reactions, together with the company Nostrum Biodiscovery (NBD) that will provide its experience in protein tailoring, required for successful application in the plastic sector and biotechnology valorization. Then, evaluation of the above applications for the enzymatic synthesis and recycling of plastic building blocks and polymers will be performed by the Technological Institute of Plastics AIMPLAS (Chemical Technology and other departments) acting as a link with the companies UNEMSA (interested in furanic plastic adhesives), ACTECO (a plastic-recycling company) and the above mentioned NBD.

euCanSHare is a joint EU-Canada project to establish a cross-border data sharing and multi-cohort cardiovascular research platform. Specifically, the project will integrate data infrastructures, IT solutions and data sources from EU, Canada and other countries into a web-based data access system with functionalities for increased efficiency in cardiovascular data-driven research. euCanSHare integrates more than 35 Canadian and European cohorts making up over 1 million records and actively seeks to expand to other regions.
The main activities advanced by NBD are to explore possible relationships between genotype (genetic change), protein mutations and their corresponding cardiovascular disease phenotypes. Using the European and Canadian cohorts data we are finding proteins statistically linked to the onset of CVD and matching them to their structures in the PDB (Protein Data Bank). The identified structures are being studied at the moment as well as a range of personalized variants following hints derived from the genomics studies in the euCanSHare virtual platform. A series of simulations (using HPC resources) are ongoing to explore the flexibility and molecular recognition of the proteins in different settings (wild type, pathological, genomic variants related to population sub- groups, etc). The results from the simulated structures will then be used for in silico virtual screening campaigns in search of new chemical entities.
Our study is particularly focused on the MAPKinases signalosome, but the principles used could be used by others to find other interesting targets through the euCanSHare platform.

OLIGOFASTX: Comprehensive platform for the sustainable development of oligonucleotide-based therapies
The OLIGOFASTX project pursues, as a general objective, to create a comprehensive platform for the development of new targeted therapies based on oligonucleotides for the treatment of rare diseases without medical response. Two of the greatest challenges facing these therapies lie in the low stability of these molecules in the blood, compared to other pharmaceutical compounds, and the development of new strategies for the synthesis of oligonucleotides that are more respectful of the environment. From NBD, a reference company in the development of in silico methods for the characterization of therapeutic compounds, the modeling of the impact of chemical modifications on the stability and activity of therapeutic oligonucleotides is proposed, thus reducing the number of molecules to be synthesized with the consequent cost reduction. On the other hand, NBD will fine-tune innovative strategies for the synthesis of naked and modified oligonucleotides using molecular modeling techniques for biocatalytic reactions, improving the processes for the synthesis and purification of oligonucleotides currently available.

Research of a new vaccine for human respiratory disease (VSRVAC)
The general objective of the project is to investigate a new vaccine based on mRNA transported in nanoparticles against RSV, which is capable of inducing dominant, effective and long-term memory cell responses against the virus.
NBD, a reference company in the in-silico design of biomolecules, will participate in the molecular research, engineering and optimization of the immunogenic potential of the encoded protein. This will require the investigation and implementation of bioinformatic tools and/or computational models aimed at describing the processes that activate and modulate the immune response against the vaccine. NBD will adapt the methodologies developed into software modules capable of being integrated into the NBD computing platform, thus transforming into new business solutions.

BioExcel is the leading European Centre of Excellence for Computational Biomolecular Research. Established in 2015, the centre has grown into a major research and innovation hub for scientific computing. BioExcel develops some of the most popular applications for modelling and simulations of biomolecular systems. A broad range of additional pre-/post-processing tools are integrated with the core applications within user-friendly workflows and container solutions. The software stack comes with great performance and scalability capabilities for extreme-scale utilization of the worlds largest high-performance computing (HPC) and high-throughput computing (HTC) compute resources. BioExcel has developed an extensive training program to address competence gaps in extreme-scale scientific computing for beginners, advanced users and HPC/HTC system maintainers. The centre maintains an extensive and growing network of industrial researchers in the pharmaceutical, chemical and food industries, and offers tailored products and consultancy services, while code development is done in close collaborations with hardware and software vendors to ensure compatibility and support for cutting-edge features. BioExcel works closely with various governmental, non-profit, educational and policy projects and initiatives.
Nostrum is involved in different areas of BioExcel-3 with special focused in the users support and engage.

After decades of development and a Nobel prize, Molecular Dynamics (MD) has reached maturity. It is no longer an exotic technique used by a small group of theoreticians but rather a method extensively used by a very large community of users. Millions of supercomputer hours are devoted to collecting trajectories, thus producing a deluge of simulation data that the community is unable to handle. A poor tradition of data sharing and the lack of appropriate infrastructures to do so lead to the loss of data after limited analysis that most likely revealed only a small fraction of the information contained. Sparse initiatives to build trajectory repositories have encountered difficulties related to: i) the lack of trust of the community in the reliability of the data deposited; ii) the lack of interoperable standards and simulation ontologies; iii) uncertainties regarding the database technology required; v) difficulties of the users to interact in an open manner with the data; and vi) disconnection of the MD-field with neighboring communities. The MDDB projects intends to design a European-scale repository of MD simulation (and associated analysis tools), which will: i) optimize computational resources; ii) favor the analysis (and meta-analysis) of trajectories for many different perspectives and fields; iii) guarantee a fast and efficient interchange of information between groups; and iv) facilitate the integration of the MD simulation field into neighboring communities. The overall result will be a more efficient use of MD and the integration of the MD field into mainstream biology and chemistry research.

NC-p38i aims at delivering new compounds to ameliorate cardiac injury induced by ischemia-reperfusion and to protect cancer patients against the cardiotoxicity induced by chemotherapy, through a common mechanism.
Cardiovascular diseases are the leading cause of death globally and entail one of the major economic challenges of public healthcare worldwide. Among them, ischemic heart disease is the most prevalent cardiovascular disorder and the most common cause of debilitating disease and death for population over 65 years old in western cultures. The incidence rate on this particular disease increases significantly with age, and current therapies do not efficiently manage and reduce the damage associated to this condition. In this context, NC-p38i intends to explore the therapeutic potential of inhibiting specific functions of p38α in cardiomyocytes, which can lead to a variety of cardiovascular diseases, such as heart failure.
Cardiac muscle cell death is a common feature of both ischemia-reperfusion injury and chemotherapy-associated cardiotoxicity. These pathologies involve both oxidative stress processes and a specific mechanism of p38α activation that implies autophosphorylation. This alternative p38α activation pathway occurs mainly in cardiomyocytes, and inhibitors of p38α have been reported to reduce cardiomyocyte death both in vitro and in vivo. Despite the therapeutic potential associated with p38α inhibition, none of the developed inhibitors has progressed beyond phase II clinical trials due to low efficacy and undesirable effects. Most of the compounds that failed in clinical trials are ATP competitors, which kill the kinase activate, and targeting the alternative activation mechanism of p38α for therapeutic purposes has barely been explored.
Our previous work in this field allowed us to identify in silico and validate in biochemical assays several hits specifically targeting this alternative mechanism of p38α activation with high selectivity and good potency. Preliminary results using rat and human cardiomyocytes in culture suggest that these compounds reduce cell death induced by simulated ischemia-reperfusion, and may display a cardioprotective role on doxorubicin-induced toxicity. However, these compounds showed some undesired toxicity in vivo. To address this issue, several new compounds were designed in silico and synthesized including modifications that maintain the ability to inhibit p38α autophosphorylation but did not show side-effects in animals. In consequence, the present project intends to progress and finish the lead optimization phase. We will focus on the in vivo characterization of this new series of compounds that have the desired biochemical activity and display reduce toxicity in animals, using ex-vivo and in vivo models of cardiac diseases, including aged animals. In addition, further analogues will be designed, synthesized and tested to improve the potency and drug-like properties of the compounds. We aim at advancing the derisking of these new compounds having in mind its transfer to market, thus answering both unmet medical needs: ischemia-reperfusion injury and chemotherapy-induced cardiotoxicity.

Recent Nobel Prize-winning discoveries on circadian clock (CC) have laid the foundation for ground-breaking approaches to treat many diseases, including Alzheimer’s disease (AD). AD is a current public health priority. Amplifying the demographic burden of the rising numbers of patients is the low success rate of AD therapies. Given that CC genes regulating memory, sleep, and neurodegeneration have altered expression profiles in AD, CC has recently emerged as a viable therapeutic target for new effective drugs. However, how to develop them remains a fundamental challenge. The “Targeting Circadian Clock Dysfunction in Alzheimer’s Disease” Doctoral Network (TClock4AD) is proposed to create a new generation of researchers able to face such challenge by harnessing neurobiology, medicinal chemistry, pharmaceutical nanotechnology, neuroimmunology, big data, bioinformatics, and entrepreneurship. TClock4AD will exploit unique expertise and advanced technologies at 10 leading universities, 3 research centers, a hospital, 10 non-academic institutions including SMEs, a large pharma company, a Health industry association, and a patient organization across EU, UK, Israel, USA and China. TClock4AD will deliver double degrees to 15 doctoral candidates, with triple-i knowledge/skills, broad vision and a business-oriented mindset. Their research activities will be structured around 5 scientific themes to: (1) develop novel artificial intelligence-, proteolysis targeting chimeras- and multitarget-based strategies for new CC drug candidates (2) develop novel drug delivery nanotechnologies, which take into consideration CC (3) investigate innovative in vitro (stem-cells, 3D cultures) & in vivo (Drosophila), as well as organ-on-chip techniques, for preclinical validation of CC drugs (4) get insight into the molecular mechanisms underlying CC in AD and associated drug response in mice and C. elegans models (5) develop innovative biotech business model and exploitation strategies.