EU-OPENSCREEN-chemical tools for the studyof plant biology and resistance mechanisms.

Item Type Article

Authors Meiners, Torsten; Stechmann, Bahne; Frank, Ronald

Citation EU-OPENSCREEN-chemical tools for the study of plant biologyand resistance mechanisms. 2014, 7 (4):113-8 J Chem Biol

DOI 10.1007/s12154-014-0118-9

Journal Journal of chemical biology

Download date 09/06/2018 00:02:22

Link to Item http://hdl.handle.net/10033/620739

NOTES

EU-OPENSCREEN—chemical tools for the study of plantbiology and resistance mechanisms

Torsten Meiners & Bahne Stechmann & Ronald Frank

Received: 8 April 2014 /Accepted: 8 July 2014 /Published online: 31 July 2014# The Author(s) 2014. This article is published with open access at Springerlink.com

Abstract EU-OPENSCREEN is an academic research infra-structure initiative in Europe for enabling researchers in all lifesciences to take advantage of chemical biology approaches totheir projects. In a collaborative effort of national networks in16 European countries, EU-OPENSCREEN will developnovel chemical compounds with external users to addressquestions in, among other fields, systems and network biology(directed and selective perturbation of signalling pathways),structural biology (compound-target interactions at atomicresolution), pharmacology (early drug discovery and toxicol-ogy) and plant biology (response of wild or crop plants toenvironmental and agricultural substances). EU-OPENSCREEN supports all stages of a tool developmentproject, including assay adaptation, high-throughput screen-ing and chemical optimisation of the ‘hit’ compounds. All toolcompounds and data will be made available to the scientificcommunity. EU-OPENSCREEN integrates high-capacityscreening platforms throughout Europe, which share a ratio-nally selected compound collection comprising up to 300,000(commercial and proprietary compounds collected fromEuropean chemists). By testing systematically this chemicalcollection in hundreds of assays originating from very differ-ent biological themes, the screening process generates enor-mous amounts of information about the biological activities ofthe substances and thereby steadily enriches our understand-ing of how and where they act.

Keywords High-capacity screening . European researchinfrastructure . Tool development . Compound collection .

Open access . Biological assays

Introduction

Small molecules have many advantages over proteins ornucleic acid-based agents for studying biological systems;for instance, they are chemically well defined and can beprovided in reproducible quality; small molecules can alsobe chosen to be cell-permeable and selectively modulate in-tracellular processes in an instant and reversible competitivefashion with their cellular targets. Many fundamental ques-tions about the molecular mechanisms which underlie biolog-ical processes can be addressed advantageously—and some-times exclusively—by using chemical tools. Over the pastdecades, gene technology approaches have brought aboutmultiple ways in which to manipulate biological systems.However, although numerous genetic resources and tools areavailable, many biological processes and pathways cannot beaddressed appropriately via genetic means due to gene redun-dancy and/or embryonic lethality. Small molecules can over-come these limitations because their application can be readilydosed and controlled in a temporal and spatial manner.

Principles of biological processes hold true across all livingspecies, be they humans, animals, bacteria, fungi, worms,plants, fish, algae, viruses etc. The search for novel chemicaltools is thus very similar and a major access route is to developan assay specific for the target under study and to use a facilitywhere the assay can be screened against a collection of com-pounds to find an active substance, or a ‘hit’. After this, achemist will often need to improve the properties of that hit tomake it a useful tool compound.

Currently, large-scale chemical biology initiatives almostexclusively focus on human disease mechanisms, while the

T. Meiners : B. Stechmann : R. Frank (*)Leibniz-Institut fuer Molekulare Pharmakologie (FMP),Robert-Roessle-Strasse 10, Berlin 13125, Germanye-mail: frank@fmp-berlin.de

T. MeinersHelmholtz-Centre for Infection Research (HZI), Inhoffenstrasse 7,Braunschweig 38124, Germany

J Chem Biol (2014) 7:113–118DOI 10.1007/s12154-014-0118-9

application of the small molecule approach in other life sci-ences is lagging. Therefore, EU-OPENSCREEN, a pan-European infrastructure initiative to support academic re-search in chemical biology, expressly advocates for the wideruse of chemical tool compounds and will serve projects fromdisciplines in which scientists have not yet tapped the fullpotential of chemical biology, such as plant biology, marineand microbial biology and ecology.

The results of this chemical biology research will primarilyprovide a deeper knowledge of how biological processes andwhich cellular targets can be selectively influenced and theconsequences of this for entire cells, species and ecologicalsystems. Understanding how chemicals, both natural and ar-tificial substances, affect our lives and environment, is also ofcritical importance for the development of new and saferproducts—be they drugs to treat diseases, herbicides to protectcrops or food additives for livestock. As such, both industryand the wider society share a great interest in chemical biol-ogy. Any chemical released into the biosphere will, in someway, interact with living species, affecting them in ways bothbeneficial and potentially adverse; a detailed knowledge abouthow chemicals act is vital for society as well as its economy,and for patients, consumers and industry.

EU-OPENSCREEN will promote innovation in two ways(Fig. 1). First, tool compounds themselves can be startingpoints for product development and directly translated intocommercial application. Secondly, tools validate their targets/processes to be ‘druggable’ which is an attractive situation forthe knowledge-driven development of innovative productsbased on target function. The intellectual property (IP) valueof the research data significantly increases during later devel-opment stages, with EU-OPENSCREEN forming the basis forgenerating valuable IP and innovation.

Need for a chemical biology infrastructure

Modern DNA sequencing technologies can rapidly read thegenomes of man or other species and unravel thousands ofnovel genes within days, but the functions of these genes (andtheir roles in diseases, for instance) remain largely unknown.The availability of suitable ‘tools’ for systematic biochemicalinvestigation of their function is severely lagging.

One major route for the discovery of bioactive substances isthe systematic empirical screening of large compound collec-tions with dedicated bioassays that have been designed torespond with a robust signal to an anticipated biological activ-ity. This approach, commonly applied by industry, is technical-ly and logistically demanding and requires large, dedicatedfacilities with expensive instrumentation and experienced per-sonnel which are unavailable to many researchers. Severalacademic institutions have recently established such high-techscreening facilities in Europe to support interdisciplinary

research projects between chemists and biologists. It is theobjective of EU-OPENSCREEN to integrate these facilitieswithin a truly pan-European structure, similar to the NIH’sMolecular Libraries Probe Production Centers Network(MLPCN) [2]. This would generate the critical mass to cost-effectively develop novel tools to the benefit of the scientificcommunity and society. A pan-European infrastructure to sup-port academic research in chemical biology, with the name ofEU-OPENSCREEN, is currently under development.

European strategy forum on research infrastructures(ESFRI)

Established in 2002 by the EU Competitiveness Council andthe research ministers of the European member states, ESFRIdeveloped a European Strategic Roadmap for ResearchInfrastructures that are ‘vital to the excellence of researchand innovation in Europe’. With the inclusion of EU-OPENSCREEN on the roadmap, ESFRI grants chemical bi-ology a high priority along with 12 other research fields in thethematic area of biological andmedical sciences, ranging frombioinformatics, structural biology and bio-banking to ecosys-tems, marine and microbial diversity (European StrategyForum on [10]). EU-OPENSCREEN, currently in its prepa-ratory phase and funded by the European Commission, buildson national networks in 16 European partner countries andtheir expert facilities with many years of proven high-qualityservices (Fig. 2). The funding for the construction and

Fig. 1 Research output and impact on innovation at the EU-OPENSCREEN infrastructure

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operation of this research infrastructure will mainly be pro-vided by individual member states. As of July 2014, tencountries and the EMBL-EBI have expressed their interestin participating in EU-OPENSCREEN by signing a memo-randum of understanding. EU-OPENSCREEN plans to createa European Research Infrastructure Consortium (ERIC) legalentity.

Chemical biology infrastructure concept

EU-OPENSCREEN is dedicated to accelerating the discoveryof biologically active substances in all areas of life sciencesand has developed a process and structure for its serviceactivities involving a multitude of research centres and a widerange of technologies and expertise, in order to optimallyserve the broader biological community. The concept is to:(i) build a central joint chemical compound collection(European Chemical Biology Library, ECBL) that draws onan abundant and relevant chemical diversity to form a uniqueresource, (ii) distribute this collection to the European partnerfacilities which are experts in their distinct themes and em-bedded in excellent research centres, (iii) support outstandingresearch projects by channelling these through a central hub tothe most appropriate facilities in Europe and (iv) unite allinformation generated from the projects in a central database(European Chemical Biology Database, ECBD) and makedata and tools available to the public (Fig. 3). The compoundcollection will be managed (storage, QC, distribution of com-pounds to the service sites) in a central compound collectionmanagement facility. Partner institutes will adhere to the bestoperational standards so as to enable cross-experiment dataanalyses. A central office manages the operation of the re-search infrastructure and the user access, and serves as thesingle contact point for users.

All compounds entering the compound collection will bequality controlled by established analytical methods (liquidchromatography–mass spectrometry, LC-MS) and character-ized for a standard set of properties (bioprofiling); around 40data points will be measured for each compound coveringchemical, biophysical, cellular cytotoxic, antimicrobial andother activities. Chemists donating their compounds will in-stantly receive this information on the property profiles oftheir substances as a compensation for their donations.

Producing and handling libraries of chemicals involvesdealing with a high degree of complexity not only duringcollection, validation and curation of the libraries, but alsowhen generating the chemical complexity with the chemicalspace of the collection. Chemical diversity is a widely appliedconcept to select structurally diverse subsets of moleculeswith the aim of maximizing the number of hits in biologicalscreening [8]. While many methods exist in the area, fewsystematic comparisons using current descriptors in particularwith the objective of assessing diversity in bioactivity spacehave been published. Koutsoukas et al. [8] compared 13widely used molecular descriptors and assessed both the sim-ilar behaviour of the descriptors in assessing the diversity ofchemical libraries, and their ability to select compounds fromlibraries that are diverse in bioactivity space, which is aproperty of much practical relevance in screening librarydesign.

The ECBL will be composed with respect to maximaldiversity/coverage of chemical space, aiming at providing hitsof a large spectrum of druggable targets. The conception,sources and characteristics of the ECBL are detailed in [7].Here, it is explained how the selection task of 200,000 mole-cules out of a pre-filtered set of 1.4 million candidates wasshared by five independent European research groups fromthe EU-OPENSCREEN consortium, each picking a subset of40,000 compounds according to their own in-house method-ology and expertise. The descriptor vectors used had included

Fig. 2 EU-OPENSCREENnational networks for chemicalbiology

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binary fingerprints, substructure/pharmacophore patterncounts or descriptors of predicted molecular properties, im-plicitly substituting the typical CS by a property space in orderto maximize the number of represented molecular scaffolds/substructures [7]. The compound selections contributed by thevarious participating groups were mapped onto general-purpose self-organizing maps built on the basis of marketeddrugs and bioactive reference molecules. In this way, theoccupancy of chemical space by the EU-OPENSCREENlibrary could be directly compared to distributions of knownbio-actives of various classes [7].

Focusing its efforts with those of other continents EU-OPENSCREEN has s tar ted a coopera t ion wi thCompounds Australia— Australia’s national collection ofsubstances [11] to provide European researchers withaccess to compounds formulated by Australian chemistsand vice versa.

EU-OPENSCREEN will implement an open-accesspolicy to encourage maximal data dissemination and pub-lication, where the same rules will apply to users fromacademia and industry alike. An optional 18-month em-bargo period to withhold the data is permitted in order toallow for translation of research results. Together withsibling initiatives of the biological and medical infrastruc-tures on the ESFRI roadmap, EU-OPENSCREEN hasdeveloped a position paper on the principles of datamanagement and sharing among European ResearchInfrastructures [3].

EU-OPENSCREEN ’s database— the EuropeanChemical Biology Database (ECBD), hosted at theEuropean Bioinformatics Institute in Hinxton, UK, will

contain validated output from the screening centres in apublic and pre-release form, offering citable links back tothe originator laboratories for primary raw data. It offers aweb portal (https://www.eu-openscreen-data.eu/) withsearch and analysis capabilities and is designed toensure the maximal availability, reuse and analysis ofdata. One of the most central standards that will beadopted by ECBD is the use of the s tandardInternational Chemical Identifier (InChI). This has rapidlybecome the worldwide de facto standard for organicsmall-molecule structure representation and allows forcompounds to be simply normalised within the ECBD,and then, for these representations to be straightforwardlyintegrated with other chemical resources on the internetsuch as for structure–activity relationship (SAR) studies(ChEMBL), chemical structure (PubChem) and target(UniProt) resources. ChEMBL is an open data databasecontaining binding, functional and ADMET information(from >5 million bioactivity measurements and >5,000protein targets) for a large number (>1 million) of drug-like bioactive compounds (see [6] for a detailed descrip-tion). It can be accessed through a web-based interface,data downloads and web services at: https://www.ebi.ac.uk/chembldb.

Tool development projects will be selected accordingto scientific novelty and excellence. EU-OPENSCREENwill support these projects through assay development,screening and follow-up chemical optimisation as wellthrough as biological validation (Fig. 4) and will thusmake high-quality tool compounds available to the sci-entific community.

Fig. 3 Organisation scheme ofthe distributed researchinfrastructure EU-OPENSCREEN (see text forexplanations)

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EU-OPENSCREEN and the resistance challengein agriculture

In plant sciences, chemical biology represents a powerful toolfor studying plant biology. Plant chemical biology is theapplication of bioactive small molecules to study cellularnetworks and developmental processes in plants. In recentyears, plant scientists have successfully used ‘chemical tools’to address fundamental questions about plant biology, such asintracellular transport processes, cell wall biology, and planthormone signalling (reviewed in [1]). These synthetic mole-cules have the potential to be developed as agrochemicalleads, while vice versa, the research on agrochemicals hasgenerated plant chemical biology knowledge and tools forbasic research [12].

The EU-OPENSCREEN infrastructure for chemical biologycan help to address the resistance challenge in agriculture bygenerating chemical tools for understanding resistance mecha-nisms and by identifying new modes of action unaffected byresistance. It can thus help to satisfy the need for effectiveresearch into new crop-protection compounds by seeking novelactive ingredients and by improving the identification processof new targets. All of this is necessary because losses inagricultural yields caused by insect damage, fungal pathogensand competition by weeds is in the range of 13–15 % for eachof these three detrimental agents and new chemical tools areneeded to combat them and reduce yield losses [4]. The urgen-cy of this problem is illustrated by the fact that no chemistrieswith a new mode of action have been introduced as herbicidesin the last 30 years [5]. Moreover, resistance of agriculturalweeds and pests to chemical control is a problem of growingimportance and serious consequences. Cutting-edge develop-ments in the design and synthesis of agrochemicals help totackle today’s challenges of weed and pest resistance [9].

An alternative crop-protection strategy is the application ofchemicals that exert their biological effects not in the

pathogen, but rather directly in the plant treated, e.g. bymimicking plant hormones and priming plant defence re-sponses to elicit protection against fungal and bacterial path-ogens or insect pests. Besides crop-protective substances,chemical compounds can also be used as plant growth regu-lators for plants and yield improvement by inducingfavourable phenotypes [12]. One example is compounds thatinterfere with ethylene responses and have a useful applicationin the post-harvest quality of fruits and vegetables [13].

Taking into consideration the recent contributions of smallmolecules to plant biology and agrochemical products, it isevident that access to novel and unique chemistries andconnecting these to physiologically relevant processes in plantassay systems will open up new avenues to novel chemicaltools tailored to plant biology and potential agrochemicalapplications. While the agrochemical industry has built upand successfully used modern agrochemical research plat-forms for high-throughput screening (HTS) during the last15 years [4], EU-OPENSCREEN offers academia and smalland medium enterprises its infrastructure as a platform andattractive option for HTS. The hundreds of screens performedat EU-OPENSCREEN will generate broad knowledge on thebioactivities of chemicals and the responses of biologicalsystems (cells, tissue, plants, invertebrate and vertebrate ani-mals) upon challenge with these chemicals. This knowledge isaccessible in the ECBD (https://www.eu-openscreen-data.eu)and can be used to predict the eco-toxicity of potential leads.EU-OPENSCREEN will use the significant expertise availableat specialised partner screening sites to support users from thefield of plant chemical biology when it starts operating as apermanent European Research Infrastructure Consortium in2016. First calls for projects will be released end of 2015.

Acknowledgments The authors wish to thank the members of the EU-OPENSCREEN consortium for contributing their expertise and help inthe planning and construction of the infrastructure. The EU-

Fig. 4 EU-OPENSCREEN willoffer services, resources andexpertise which support all stagesof a tool development project. Itscore activity is the systematicscreening of large diversecompound libraries (phase I) andthe chemical optimisation of theidentified compounds intovaluable tool compounds (phaseII)

J Chem Biol (2014) 7:113–118 117

OPENSCREEN consortium has received funding from the EuropeanUnion’s Seventh Framework Programme (FP7/2007–2013), grant agree-ment n 261861 (EU-OPENSCREEN).

Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use, distribution, andreproduction in any medium, provided the original author(s) and thesource are credited.

References

1. Audenaert D & Overvoorde P (eds) (2013) Plant chemical biology.John Wiley & Sons Inc, Ho-boken, New Jersey

2. Austin CP, Brady LS, Insel TR, Collins FS (2004) NIH molecularlibraries initiative. Science 306:1138–1139

3. Blomberg N, Suhr S, Meiners T (eds) (2014) Principles of datamanagement and sharing at European Research Infrastructures. http://zenodo.org/record/8304#.Uv4M6Y2Ttc. Accessed July 28, 2014

4. Drewes M, Tietjen K, Sparks TC (2013) High‐throughput screeningin agrochemical research. In: Jeschke P, Krämer W, Schirmer U,Witschelpp M (eds) Modern methods in crop protection research.Wiley-VCH, Weinheim

5. Duke SO (2012) Why have no new herbicide modes of actionappeared in recent years? Pest Manag Sci 68:505–512

6. Gaulton A, Bellis LJ, Bento AP, Chambers J, Davies M, Hersey A,Light Y, McGlinchey S, Michalovich D, Al-Lazikani B, Overington

JP (2012) ChEMBL: a large-scale bioactivity database for drugdiscovery. Nucleic Acids Res 40:D1100–D1107

7. Horvath D, Lisurek M, Rupp B, Kuehne R, Specker E, Kries J-P,Rognan D, Andersson CD, Almqvist F, Elofsson M, Enqvist P-A,Gustavsson A-L, Remez N, Mestres J, Marcou G, Varnek A, Hibert,Quintana J and Frank R (2014) Design of a general-purposeEuropean compound screening library for EUOPENSCREEN.Chem Med Chem. doi:10.1002/cmdc.201402126

8. Koutsoukas A, Paricharak S, Galloway WR, Spring DR, IJzermanAP, Glen RC, Marcus D, Bender A (2014) How diverse arediversity assessment methods? A comparative analysis andbenchmarking of molecular descriptor space. J Chem InformModel 54:230–242

9. Lamberth C, Jeanmart S, Luksch T, Plant A (2013) Current chal-lenges and trends in the discovery of agrochemicals. Science 341:742–746

10. European Strategy Forum on Research Infrastructures (2010)Biological and medical sciences thematic working group Report2010. http://ec.europa.eu/research/infrastructures/pdf/bms_report_en.pdf. Accessed July 28, 2014

11. Simpson M, Poulsen S-A (2014) An overview of Australia’s com-pound management facility: the Queensland Compound Library.ACS Chem Biol 9:28–33

12. Walsh TA (2013) Prospects and challenges for translating emerg-ing insights in plant chemical biology into new agrochemicals.In: Audenaert D, Overvoorde P (eds) Plant Chemical Biology.Wiley, Hoboken

13. Watkins CB (2006) The use of 1-methylcyclopropene (1-MCP) onfruits and vegetables. Biotech-nol Adv 24:389–409

118 J Chem Biol (2014) 7:113–118