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Open-acess Medicinal Chemistry Centre (OpenMedChem)

Grant number: 14/50897-0
Support type:Research Projects - Thematic Grants
Duration: July 01, 2017 - June 30, 2023
Field of knowledge:Biological Sciences - Biology
Cooperation agreement: CNPq - INCTs
Principal Investigator:Paulo Arruda
Grantee:Paulo Arruda
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Co-Principal Investigators:Andrei Leitão ; Carlos Henrique Tomich de Paula da Silva ; Cleslei Fernando Zanelli ; João Renato Carvalho Muniz ; Jonathan Mark Elkins ; Katlin Brauer Massirer ; Opher Gileadi ; Rafael Lemos Miguez Couñago
Associated grant(s):18/22363-1 - Macrocyclic compounds as strategy for kinase-related chemical probe development, AP.R SPRINT
Associated scholarship(s):19/11320-2 - Cellular investigation of protein kinases involved with splicing, by minigene system, BP.IC
19/11884-3 - RNA targets and cellular function profiling of the RNA-binding protein Bicaudal C homolog 1 (BICC1), BP.IC
19/14275-8 - Structural analysis of the kinase proteins PRPF4 and DYRK1B, from the CMGC family, and identification of small compound inhibitors, BP.PD
+ associated scholarships 18/16672-1 - Structural determination and search for inhibitors of the enzyme deoxy-hypusine synthase of eukaryotic organisms that cause Neglected Tropical Diseases, BP.DR
18/06442-9 - Discovering new kinases and receptor-like kinases associated with the response to drought stress in maize, BP.PD
17/19609-6 - Discovery of new kinases associated with water stress response in maize, BP.PD
17/17575-7 - Computational structure, electronic notebook and database design, BP.TT - associated scholarships

Abstract

Many of the discoveries from the rapidly expanding genomic sciences are not effectively utilized in medicine, agriculture and industry. This is partly because of the disconnection between scientists in different disciplines, and because much of the translational research done in both industry and academia is patent-protected and not published in a timely manner. This INCT proposal addresses both these challenges. Firstly, by creating a highly integrated network of researchers in different disciplines: genetics, protein biochemistry, medicinal chemistry, cell- and developmental biology; and second, by committing to open- access research: all data and reagents will be made available to all without restrictions. The INCT aims to unlock the potential of genes relevant for medicine by focusing on the proteins encoded by these genes, and developing a package of tools that enable research on these proteins. The package of research tools might indude expression dones, protein purification protocols, antibodies, crystal structure and a chemical inhibitor. These target-enabling packages (TEPs) will provide the research community with a mechanism to greatly expand their capabilities. To ensure that Brazilian scientists benefit from these tools, our INCT is committing to make them available with no strings attached to all interested researchers. Our INCT is focusing on enabling protein research because protein research is often the “missing link" between genetics and biological functional studies. The proteins encoded by common and mutant disease-related genes, or proteins that are targets for anti- parasitic drugs are often not studied because reagents and tools are not available. Our INCT will overcome this major hurdle to translational science. The INCT will be organized around a core laboratory in UNICAMP, in collaboration with the Structural Genomics Consortium (SGC; www.thesgc.org) (SGC-UNICAMP) and its laboratories at the University of Oxford (SGC-Oxford) and the University of Toronto (SGC-Toronto). Collaborating groups within the INCT network will nominate a list of target genes, based on their research interest. The INCT Core group will done and purify, crystallize and determine the atomic structures of the encoded proteins. Then, the Core and groups within the network will collaborate to develop functional assays for the activity of each protein (e.g. enzymatic, ligand-binding or protein-binding), aiming to understand the function of the proteins. The core lab will optimize the assays for small-molecule screens, and will perform such screens to find chemical starting points for inhibitor development, and will develop chemical probes in collaboration with INCT network scientists in academia and industry. The knowledge and reagents generated from the protein-Ievel studies will be used to formulate and test hypotheses in the relevant cellular and physiological contexts. The key deliverables of the INCT are 15 "Target Enabling Packages" (TEPs), which consist of clones and methods for protein purification, crystallization and activity assays; chemical probes for use modulators of human cell function; and further information on the proteomics, the impact of mutations, and the physiology of the target proteins. TEPs will be utilized promptly by the INCT partners but it will also be published on the INCT web site and in scientific journals, with a mechanism for distribution of the clones and reagents without restrictions on use. Our INCT will collaborate not only with network scientists, but also with any laboratory in Brazil that can suggest new and important targets for research. Ali nominated targets will be prioritized by the INCT management committee. The nominating labs will then be able to use the expertise and infrastructure within the INCT to generate the proteins and initiate structural or functional studies. Each project will be evaluated on an ongoing basis and, where appropriate, developed into full-scale projects or stopped. Ali nominating groups must agree to the release of data and reagents upon completion of the projects. Once projects are accepted, chemical probe-generating collaborations will be initiated in INCT laboratories, in an open collaboration with SGC and industry partners. One innovative action of this INCT is the inclusion of nominations from and plant science. For example, key plant targets, mostly protein kinases, potentially associated to plant response to abiotic stress will enter the Centre pipeline for TEPs development. The chemical probes developed for these proteins will be used to ask questions related to plant response to abiotic stress. These tools will be made available to plant science community without restrictions. In summary, this INCT propose to create a tightly coordinated network of research groups, in collaboration with the highly successful international Structural Genomics Consortium, to promote the utilization of genetic discoveries for medicinal, plant and industrial development. (AU)

Articles published in Agência FAPESP Newsletter about the research grant
Protein involved in corn’s water stress response discovered 
Researchers join forces to combat coronavirus 
Chemical probe can help regulate an essential signaling pathway in cells 
Articles published in other media outlets (25 total):
More itemsLess items
Avanços da genômica aumentam a precisão dos diagnósticos 
Avanços da genômica aumentam a precisão dos diagnósticos 
Descoberta proteína da resposta hídrica do milho 
Descoberta proteína da resposta hídrica do milho 
Descoberta proteína que controla os mecanismos de desenvolvimento do milho 
Descoberta proteína da resposta hídrica do milho 
Proteína involucrada en la respuesta al estrés hídrico del maíz descubierta 
Descoberta proteína da resposta hídrica do milho 
Descoberta proteína da resposta hídrica do milho 
Protein involved in corn's water stress response discovered 
Protein involved in corn’s water stress response discovered 
Protein involved in corn's water stress response discovered - The protein could help develop drought-resistant plant varieties and products that reduce losses related to climate change. 
Protein involved in corn’s water stress response discovered 
Protein involved in corn’s water stress response discovered 
Protein involved in corn's water stress response discovered 
Protein involved in corn’s water stress response discovered 
Proteína envolvida na resistência do milho à seca 
DESCOBERTA PROTEÍNA ENVOLVIDA NA RESISTÊNCIA DO MILHO À SECA 
Descoberta proteína envolvida na resistência do milho à seca 
Descoberta nova proteína envolvida na resistência do milho à seca 
Descoberta proteína envolvida na resistência do milho à seca 
Descoberta proteína envolvida na resistência do milho à seca 
Descoberta proteína envolvida na resistência do milho à seca 
Descoberta proteína envolvida na resistência do milho à seca 
Chemical Probe can Regulate Signalling Pathway and Block Cell Invasion by Arboviruses 

Scientific publications (8)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DA SILVA, VIVIAM M.; CABRAL, ALINE D.; SPERANCA, MARCIA A.; SQUINA, FABIO M.; MUNIZ, JOAO RENATO C.; MARTIN, LYDIE; NICOLET, YVAIN; GARCIA, WANIUS. High-resolution structure of a modular hyperthermostable endo-beta-1,4-mannanase from Thermotoga petrophila: The ancillary immunoglobulin-like module is a thermostabilizing domain. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1868, n. 8 AUG 2020. Web of Science Citations: 0.
BARRETO, PEDRO; COUNAGO, RAFAEL M.; ARRUDA, PAULO. Mitochondrial uncoupling protein-dependent signaling in plant bioenergetics and stress response. MITOCHONDRION, v. 53, p. 109-120, JUL 2020. Web of Science Citations: 0.
WELLS, CARROW I.; VASTA, JAMES D.; CORONA, CESEAR R.; WILKINSON, JENNIFER; ZIMPRICH, CHAD A.; INGOLD, MORGAN R.; PICKETT, JULIE E.; DREWRY, DAVID H.; PUGH, KATHRYN M.; SCHWINN, MARIE K.; HWANG, BYOUNGHOON (BRIAN); ZEGZOUTI, HICHAM; HUBER, KILIAN V. M.; CONG, MEI; MEISENHEIMER, PONCHO L.; WILLSON, TIMOTHY M.; ROBERS, MATTHEW B. Quantifying CDK inhibitor selectivity in live cells. NATURE COMMUNICATIONS, v. 11, n. 1 JUN 2 2020. Web of Science Citations: 0.
AQUINO, BRUNO; DA SILVA, VIVIANE C. H.; MASSIRER, KATLIN B.; ARRUDA, PAULO. Crystal structure of DRIK1, a stress-responsive receptor-like pseudokinase, reveals the molecular basis for the absence of ATP binding. BMC PLANT BIOLOGY, v. 20, n. 1 APR 15 2020. Web of Science Citations: 0.
SCOTT, FIONA; FALA, ANGELA M.; PENNICOTT, LEWIS E.; REUILLON, TRISTAN D.; MASSIRER, KATLIN B.; ELKINS, JONATHAN M.; WARD, SIMON E. Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer. Bioorganic & Medicinal Chemistry Letters, v. 30, n. 8 APR 15 2020. Web of Science Citations: 0.
WELLS, CARROW; COUNAGO, RAFAEL M.; LIMAS, JUANITA C.; ALMEIDA, TUANNY L.; COOK, JEANETTE GOWEN; DREWRY, DAVID H.; ELKINS, JONATHAN M.; GILEADI, OPHER; KAPADIA, NIRAV R.; LORENTE-MACIAS, ALVARO; PICKETT, JULIE E.; RIEMEN, ALEXANDER; RUELA-DE-SOUSA, ROBERTA R.; WILLSON, TIMOTHY M.; ZHANG, CUNYU; ZUERCHER, WILLIAM J.; ZUTSHI, REENA; AXTMAN, ALISON D. SGC-AAK1-1: A Chemical Probe Targeting AAK1 and BMP2K. ACS Medicinal Chemistry Letters, v. 11, n. 3, p. 340-345, MAR 12 2020. Web of Science Citations: 0.
O'BYRNE, SEAN N.; SCOTT, JOHN W.; PILOTTE, JOSEPH R.; SANTIAGO, ANDRE DA S.; LANGENDORF, CHRISTOPHER G.; OAKHILL, JONATHAN S.; EDUFUL, BENJAMIN J.; COUNAGO, RAFAEL M.; WELLS, CARROW I.; ZUERCHER, WILLIAM J.; WILLSON, TIMOTHY M.; DREWRY, DAVID H. In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds. Molecules, v. 25, n. 2 JAN 2 2020. Web of Science Citations: 1.
PROFETA, GERSON S.; DOS REIS, CAIO V.; SANTIAGO, ANDRE DA S.; GODOI, PAULO H. C.; FALA, ANGELA M.; WELLS, CARROW I.; SARTORI, ROGER; SALMAZO, ANITA P. T.; RAMOS, PRISCILA Z.; MASSIRER, KATLIN B.; ELKINS, JONATHAN M.; DREWRY, DAVID H.; GILEADI, OPHER; COUNAGO, RAFAEL M. Binding and structural analyses of potent inhibitors of the human Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2) identified from a collection of commercially-available kinase inhibitors. SCIENTIFIC REPORTS, v. 9, NOV 11 2019. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.