Under this call EU-OPENSCREEN-DRIVE offers funding to enable transnational access to chemical proteomics and compound disposition study facilities. A total of 6 projects will be selected in two separate calls (May 2019 and April 2021). Users from institutions within European Member States and Associated countries and up to one user from a non-EU country will have the possibility to apply to access 7 advanced proteomics and Mass Spectrometry Imaging (MSI) facilities across Europe.
The EU-OPENSCREEN-DRIVE Chemoproteomics and Mass Spectrometry Imaging (MSI) Call 2021 aims at increasing the understanding of mechanisms of action by which a tool or small molecule hit/lead compound exerts its pharmacological effect. The users are offered access to target-based and phenotype-based workflows, proteomics and related advanced mass spectrometry-based technologies, with focus on MSI. EU-OPENSCREEN-DRIVE chemistry partner sites together with partners with proven track-records in probe development, target deconvolution and MSI will support at least 3 successful applicants providing collaboration on target identification and compound disposition studies. Under this call, applicants will have the opportunity to access a broad range of experimental approaches through different chemical proteomic workflows for samples of bacterial and mammalian origin or in whole organisms (e.g. multicellular parasites). Preference will be given to projects using MSI and/or involving synthesis of chemical probes for affinity-based target identification.
Applicants will be asked to provide a detailed description of the objectives of their project, and to fulfil specific pre-requisites such as i) confirmed compound cellular or organismal activity in the low µM range; ii) ideally (but not mandatory) preliminary Structure Activity Relationships (SAR) identified; iii) ideally (but not mandatory) having an SAR-informed synthesis of linker derivatives for functional immobilization in place; iv) ideally (but not mandatory) having an inactive compound from the same series available, v) ideally, for MSI studies, having a well-characterised pharmacokinetic profile (e.g. half-life, bioavailability, maximum tolerated dose, dosing route, initial formulation) and v) granted access to relevant biological material. All project pre-requisites for application can be found below.
Call 2 for proposals will be open until May 17th 2021 (16:00 CET). Eligible proposals will be evaluated for technical feasibility, scientific excellence and impact. The successful projects will be allocated upon evaluation to the most appropriate EU-OPENSCREEN-DRIVE chemoproteomics pipeline according to the strengths of specific methodology and expertise of the facilities, ensuring the requirement of transnationality. Please see below to learn more about our partner sites. Proposals will be handled confidentially. Read more about the proposal submission, eligibility criteria, modality of access and evaluation processes below.
During the first EU-OPENSCREEN-DRIVE Chemoprotemics Call (May-September 2019) a total of eight projects were submitted by applicants from Germany, Italy, Portugal, Spain and the United Kingdom. This call was aimed to support European researchers’ access to target-based and phenotype-based workflows, proteomics and related advanced mass spectrometry-based technologies. The research fields covered by the proposals were diverse and characterised by a broad scientific interest from mitochondrial function to immune oncology, multiple sclerosis and Leishmaniasis. Three projects with the highest scientific excellence have been selected and they are currently receiving scientific support from our sites at the Institute of Bioorganic Chemistry Polish Academy of Sciences (IBCH PAS), the Leibniz Research Institute for Molecular Pharmacology (FVB-FMP), the Department of Biotechnology and Nanomedicine at SINTEF (SIN), the University of Santiago de Compostela, Biofarma (USC) and the Technical University of Munich (TUM).
drug discovery, chemical proteomics, target identification, mass spectrometry, MS imaging, chemical probes
Start date: April-06-2021 (9:00 CET)
Closing date: May-17-2021 (16:00 CET)
indicating "EU-OPENSCREEN-DRIVE Chemoproteomics and MSI Call 2021"
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Within this call EU-OPENSCREEN-DRIVE offers transnational access to state-of-the-art chemical synthesis facilities for the production of conjugated probe molecules to support affinity-based studies:
Probe synthesis: Department of Molecular Probes and Prodrugs at IBCH PAS aims at the development of small molecule chemical tools to investigate biological models. In particular, we have an extensive experience in the development of fluorescent and bioluminescent probes to sense biochemical analytes in vitro and in live cells and more complex cellular models. In addition, through a thorough expertise in organic synthesis we develop advanced tools for labelling (reactive probes) and controlling (prodrugs) proteins.
Within this project, IBCH PAS offers support for the synthesis of 2-3 probes for studying target engagement and/or fluorescent labelling, on the basis of one validated bioactive compound with identified activity and benign point of attachment of a potential linker on its scaffold. Probes will be composed of variable length linkers connecting a ligand (derived by the user) with a specific tag (e.g. click chemistry handle for resin-based purification or fluorophore for imaging). Synthesis will be performed in a convergent manner with several linker-tag adducts being synthesized in parallel and then attached through a stable moiety to the identified hit scaffold.
Proteomics: Centre for High Throughput Screening Studies offers access to advanced infrastructure for assay development, miniaturisation and screening of large libraries of small molecules using various modes of detection (fluorescence, luminescence, imaging and variants thereof) as well as expertise in image analysis. In connection with biological mass spectrometry facility we have an experience and are also able to provide advanced follow-up studies in proteomics and metabolomics.
Within this project, IBCH PAS provides access to the infrastructure and expertise in target identification through proteomic analysis. Both targeted and non-targeted proteomic workflows are available involving purification and mass spectrometry analysis. Available equipment includes but is not limited to MALDI/TOF/TOF, nanoLC-ESI-qOrbitrap with Advison NanoMate add-on TripleQuad LC-ESI-MS.
The department of Chemical Biology at HZI aims at discovering new antibacterial and antiviral drugs, characterizing their functionality and optimizing their properties. HZI focuses on infection research and small molecules that can function as antimicrobial or antiviral agents, interfere with pathogenicity factors or stimulate the immune system.
Within this call, HZI offers expertise in the area of drug conjugates to synthesize functionalized chemical probes. HZI has ample experience in the synthesis of bacteria-targeted conjugates that combine a targeting and an effector moiety (an antibiotic, a fluorophore, etc) through various cleavable and non-cleavable linkers. HZI will support preparation of probes for affinity-based target identification using chemoproteomics.
Within this call EU-OPENSCREEN-DRIVE offers transnational access to advanced proteomics facilities for the prosecution of affinity-based studies and MALDI-Imaging for compound disposition studies.
Partners operate state-of-the-art quantitative mass spectrometry readout capable of interrogating thousands of potential drug-protein interactions simultaneously along with the required bioinformatics tools for data analysis and QC.
SINTEF provides access to advanced mass spectrometry-based proteomics facilities for drug target interaction studies.This includes facilities for quantitative proteomics to support non-targeted and targeted screening of drug-protein interactions. Using robotic handling SINTEF offers high-throughput sample preparation (extraction, lysis, in solution digestion, FASP, SPE clean-up) for both targeted and shotgun proteomics analysis. For shotgun proteomics to support non-targeted screening of drug-protein interaction, QExactive-HF-X mass spectrometer is employed (at a Core facility). For targeted screening of identified interactions, LC-MS/MS (Agilent QQQ) analysis is offered for highly sensitive analysis of multiple peptides. Targeted screening of identified interactions in a high-throughput manner is offered using Rapidfire-MS/MS (Agilent). In targeted analysis, isotope-labelled peptide standards are employed.
Moreover, within this call SINTEF offers Mass Spectrometry Imaging (MSI) for compound disposition studies. MSI facilities at SINTEF include sample preparation set-ups (cryostat sectioning, ImagePrep for matrix and reagent deposition), and sample analysis using ultra-high-resolution mass spectrometry on a Bruker Solarix XR 12T FTICR. Analysis of resulting imaging data by multivariate statistical analysis tools is also provided (SCiLS software). The facilities offered by SINTEF using MSI support the determination of discrete tissue distribution of the parent compound, its metabolites, synthetic derivatives, as well as endogenous molecules linked to pharmacological and toxicological mechanisms of the compound.
Data processing and bioinformatics data interpretation pipelines are also offered including statistical analysis.
USC offers a proteomic facility and expertise for target identification with chemical proteomics methods. Established chemical proteomics workflows include gel-based affinity-based protein profiling and target-based screening methodologies. Specialized chemical probes to enrich proteomes (e.g. protein kinases, proteases, GPCR) are readily available for selectivity profiling of inhibitors. Fluorescence scanner, MALDI-TOF and Triple TOF LC/MS equipment is available.
Our bioinformatics infrastructure includes supercomputing and data storage capabilities (a heterogeneous cluster, with an Infiniband FDR low latency network interconnecting 317 computing nodes based on Intel Xeon Hasswell processors. Together, these nodes are able to provide a computing power of 328 TFLOPS, 44,8 TB of RAM and 1,5 PB of disk capacity. The system includes a high-performance parallel storage system able to achieve a speed of more than 20 GB/s) and can be implemented for the real-time analysis of genomics and proteomics data.
TUM Proteomics offers a broad range of advanced mass spectrometry based proteomic methods and expertise on specialized chemical proteomics technologies for drug target deconvolution. Established chemical proteomics workflows include the generation and application of affinity matrices from small molecules as well as natural compound derivatives. Specialized affinity matrices enriching subproteomes (protein kinases, HDACs) are readily available at TUM and allow for selectivity profiling of small molecule kinase and HDAC inhibitors.
In addition, TUM infrastructure provides facilities for cellular thermal shift assays (CETSA) and iso-thermal dose response (ITDR) experiments. It also provides bioinformatics infrastructure (400 TB online data storage, about 20 server computers totaling 300 CPUs and about 1 TB memory, 6 GPUs) and operates ProteomicsDB, a powerful in-memory database for the real-time analysis of proteomic data.
CeMOS combines expertise in development of measurement devices, in optics and spectroscopy and in mass spectrometry with substantial expertise in application development for the chemical, pharmaceutical, MedTech and Biotech industries. Within this call, CeMOS will provide access to Mass Spectrometry Imaging (MSI) for (quantitative) compound disposition studies, discovery and imaging of response markers and evaluation of toxicology findings. Focus areas include lipid/metabolite as well as infrared microscopy-guided MSI in fresh-frozen tissue sections, mainly in the therapy areas of oncology, neurodegenerative and metabolic diseases. MUAS offers state-of-the-art instrumentation for MSI sample preparation (HTX M5 and SunChrom sprayers) and analysis using high-resolution mass spectrometry on a Bruker solariX XR 7T FTICR and high-speed mass spectrometry on a Bruker rapifleX. Suitable data analysis tools are available (SCiLSlab and in-house bioinformatics).
Moreover, MUAS offers access to MALDI MS-based assays for drug discovery. Assay facilities include an Analytik Jena CyBio Felix pipetting robot for sample preparation and a high-speed Bruker rapifleX mass spectrometer for measurements. Assays are currently run in 384-well format and can be either biochemical assays with enzymes causing mass changes or cell-based assays where enzyme inhibition causes an accumulation of the substrate.
Applicants are required to provide the following pre-requisites for application:
Specific additional requirements for MSI-based projects:
The review process of applications consists of 2 steps of evaluation (technical and scientific). The application will remain strictly confidential throughout the review process. Reviewers will be bound by a non-disclosure agreement.
Technical evaluation of submitted proposals will be performed by internal EU-OPENSCREEN-DRIVE members involved in the chemoproteomics or MSI activities. Technical evaluation will ensure the necessary alignment between user proposals and the technical capabilities of each partner site in terms of technical feasibility. EU-OPENSCREEN-DRIVE technical reviewers will ensure that the eligibility criteria and pre-requisites for applicants are met. Moreover, they will assess that appropriate resources for the technical implementation of the projects are available.
Scientific evaluation of submitted proposals will be performed by a minimum of 2 external experts in the field of chemical proteomics or MSI. Proposals will be assessed based on the scientific excellence of the proposal, the scientific quality of the research, and impact and innovation potential of the proposed study. Societal impact and gender aspects of the project-specific research questions and method will also be considered.
Open access (gold or green) is required for any publication of access results. EU-OPENSCREEN-DRIVE funding must be clearly acknowledged by: “This project has received funding from the European Union´s Horizon 2020 research and innovation programme under grant agreement No 823893.”
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