Novel targets and new drug candidates to combat epilepsy: Design of subtype-selective spirocyclic inhibitors to distinguish among gamma-aminobutyric acid transporter protein subtypes.  Page description

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Details of project

  
Identifier
102166
Type NN
Principal investigator Kardos, Julianna
Title in Hungarian Új célpontok és gyógyszerjelöltek az epilepszia terápiájában: gamma-aminovajsav transzporter altípusokat megkülönböztető specifikus spirociklusos inhibitorok tervezése.
Title in English Novel targets and new drug candidates to combat epilepsy: Design of subtype-selective spirocyclic inhibitors to distinguish among gamma-aminobutyric acid transporter protein subtypes.
Keywords in Hungarian farmakológia, farmakogenomika, gyógyszertervezés és felfedezés, gyógyszeres terápia, szerves kémia, neurológiai betegségek
Keywords in English pharmacology, pharmacogenomics, drug discovery and design, drug therapy, organic chemistry, neurological disorders
Discipline
Neurochemistry and neuropharmacology (Council of Medical and Biological Sciences)100 %
Panel Chemistry 2
Department or equivalent Institute of Cognitive Neuroscience and Psychology (Research Center of Natural Sciences)
Participants Héja, László
Kékesi, Orsolya Sára
Simon, Ágnes
Starting date 2011-04-01
Closing date 2014-06-30
Funding (in million HUF) 32.066
FTE (full time equivalent) 4.17
state closed project
Summary in Hungarian
High-resolution crystal structures of bacterial orthologues of neurotransmitter-sodium symporters triggered a rapidly advancing global research theme on target structure-based drug design being funded by research grants as well as pharmaceuticals. We approach this field by attracting the complementary expertise of the Hungarian and Belgian party for establishing collaboration. We aim to tackle some fundamental issues related to central inhibition through specific allosteric recognition and functioning of gamma-aminobutyric acid (GABA) transporter subtypes (GATs). To this end, we plan to implement an integrated approach that combines the experience of HPI in homology modelling and screening and the expertise of BPI in chiral syntheses and molecular design. Here we wish to combine complementary expertises of Belgian and Hungarian PIs into one integrated approach in order to disclose glial GAT subtype-selective inhibitors. The question asked is how to identify and explore allosteric binding motifs of human GAT subtypes by homology modelling and predictive chemistry. The planned studies are expected to strengthen the concept of allosteric selectivity in recognition and functioning of GATs and family member transporters. Rapid progress in the proposed project is expected due to an efficient communication channel established between the two PIs prior to this proposal and because of an ideal complementary nature of the specialties of HPI and BPI. The combination of theoretical, synthetic and molecular biology techniques provides a powerful tool for successful cooperation and holds the potential of discovering novel, selective inhibitors for hGAT subtypes, which may be developed into AEDS candidates in the future.
Summary
High-resolution crystal structures of bacterial orthologues of neurotransmitter-sodium symporters triggered a rapidly advancing global research theme on target structure-based drug design being funded by research grants as well as pharmaceuticals. We approach this field by attracting the complementary expertise of the Hungarian and Belgian party for establishing collaboration. We aim to tackle some fundamental issues related to central inhibition through specific allosteric recognition and functioning of gamma-aminobutyric acid (GABA) transporter subtypes (GATs). To this end, we plan to implement an integrated approach that combines the experience of HPI in homology modelling and screening and the expertise of BPI in chiral syntheses and molecular design. Here we wish to combine complementary expertises of Belgian and Hungarian PIs into one integrated approach in order to disclose glial GAT subtype-selective inhibitors. The question asked is how to identify and explore allosteric binding motifs of human GAT subtypes by homology modelling and predictive chemistry. The planned studies are expected to strengthen the concept of allosteric selectivity in recognition and functioning of GATs and family member transporters. Rapid progress in the proposed project is expected due to an efficient communication channel established between the two PIs prior to this proposal and because of an ideal complementary nature of the specialties of HPI and BPI. The combination of theoretical, synthetic and molecular biology techniques provides a powerful tool for successful cooperation and holds the potential of discovering novel, selective inhibitors for hGAT subtypes, which may be developed into AEDS candidates in the future.




 

Final report

  
Results in Hungarian
SLC6 családba tartozó GABA transzporter altípusok (GATS) bakteriális ortológja, a LeuT szerkezetének felismerése tette lehetővé a neurotranszmitter-Na+ szimporter funkció megértésén és szerkezetén alapú gyógyszertervezésből kiinduló globális kutatási téma gyors fejlődését. A kutatási területet magyar és belga partnerek szaktudásának kombinálásával, kollaborációban közelítettük - melyet az ERA-OTKA kutatási grant támogatott. GATS allosztérikus modulációjának kombinált kémiai és biológiai megközelítésével a centrális inhibíció alapvető kérdéseit érintettünk. A projekt beszámolóban a GABA-Na+ szimport mechanizmusának mélyebb megértése továbbá szelektív spirobiciklusos GATS inhibitorok tervezése és felismerése útján elért eredményeinkről számolunk be. A spirobiciklusos származékok allosztérikus kötődését és a GABA-Na+ szimportot, monomer továbbá homodimer GATS szerkezetekben modelleztük. Párhuzamosan, tervezés – dokkolás – szintézis – in vitro hatásvizsgálat (GATS-kifejező HEK293 sejtvonalakon) vizsgálatsorozatot valósítottunk meg 3 iterációs ciklusban. Ezen az úton választ kaptunk GATS és homológjaik Na+ szimport mechanizmusának alapvető kérdéseire, továbbá négy allosztérikus szelektivitás koncepción alapuló kutatási drogot ismertünk fel. Az alkalmazott elméleti, szintetikus és molekuláris biológiai technikák iteratív kombinációja hatékony eszköze lehet a felismert GATS inihbitorok szerkezetén alapuló specifikusabb antiepileptikus gyógyszerek kifejlesztésének a jövőben.
Results in English
Disclosure of LeuT structure, a bacterial orthologue of the SLC6 family member GABA transporter subtypes (GATs) allowed a rapidly advancing global research theme on understanding neurotransmitter-Na+ symporter function and structure-based drug design. Being funded by the ERA-OTKA research grant, we kept approaching this field by attracting the complementary expertise of Hungarian/Belgian parties for establishing collaboration. Some fundamental topics related to central inhibition through the allosteric modulation of GATs were tackled combining chemical and biological methods. We report on results obtained in the reporting period via the more detailed understanding of GABA-Na+ symport together with the design and discovery of new potentially selective spirobyciclic GATs inhibitors. Issues were advanced modelling Na+ symport and allosteric binding in monomeric and dimeric GATs structures, in parallel with the implementation of a three-cycle iterative approach comprising MD, docking, synthesis and efficacy testing of spirobicyclic compounds on HEK293 cell lines expressing the four GATs. Findings answer basic questions on the symport mechanisms of GATs and homologues altogether with the design and discovery of four investigational drugs based on the allosteric selectivity concept. The above combination of theoretical, synthetic and molecular biology techniques provides a powerful tool for finding investigational drugs enabling future development of more specific antiepileptics.
Full text https://www.otka-palyazat.hu/download.php?type=zarobeszamolo&projektid=102166
Decision
Yes





 

List of publications

  
Kardos J, Héja L, Nyitrai G, Kékesi O, Simon Á, Bencsura Á: Glial GABA transporters: function and modeling, Annual Conference of the Hungarian Biochemical Society Pécs, Aug 28-31, 2011
Simon Á, Bencsura Á, Kardo J: Molecular modeling of gamma-aminobutyric acid transporter function, Fourth SFB35 Symposium on Transmembrane Transporters in Health and Disease, Vienna, Sept 8-9, 2011
Simon Á, Bencsura Á, Mayer I, Kardos J: Homology modelling of gamma-aminobutyric acid transporter dimers in the occluded and inward open states, Fifth SFB35 Symposium on Transmembrane Transporters in Health and Disease, Vienna, Sept 24-25, 2012
Héja L, Nyitrai G, Kékesi O, Dobolyi A, Szabó P, Fiath R, Ulbert I, Pal-Szenthe B, Palkovits M, Kardos J: Astrocytes convert network excitation to tonic inhibition of neurons, BMC BIOLOGY 10, 26, 2012
Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon Á, Hegedus T, Beekman JM, Lukacs GL: Mechanism-based corrector combination restores ΔF508-CFTR folding and function, NATURE CHEMICAL BIOLOGY 9, 444-454, 2013
Nyitrai G, Kékesi O, Pál I, Keglevich P, Csíki Z, Fügedi P, Simon Á, Fitos I, Németh K, Visy J, Tárkányi G, Kardos J: Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions, NANOTOXICOLOGY 6, 576-586, 2012
Héja L: Astrocytes convert network excitation to tonic inhibition of neurons, GLIA 61, S27, 2013
Kékesi O, Nyitrai G, Szabó P, Fiáth R, Ulbert I, Kardos J, Héja L: Glial GABA transporters downregulate enhanced neuronal activity, GLIA 61, S122, 2013
Simon Á, Bencsura Á, Mayer I, Kardos J: Homology modelling of gamma-aminobutyric adic transporter dimers in the occluded and inward open states, Fifth SFB Symposium 2012 Bécs, Transmembrane Transporters in Healt and Disease, 2012
Simon Á, Bencsura Á, Mayer I, Kardos J: Homology modelling of gamma-aminobutyric acid transporter dimers in the occluded and inward open states, MTA Természettudományi Kutatóközpont, Szakmai Napok Budapest, 2012, 2012
Simon A, Bencsura Á, Héja L, Kardos J: Distinguishable monomers in the major human GABA transporter homodimer model: Co-existence of occluded and pre-inward open conformations, BMC Bioinformatics, 2013
Pál I, Nyitrai G, Kardos J, Héja L: Glial and neuronal mechanisms underlying the label-free intrinsic optical signal, GLIA 61, S108, 2013
Kardos J: Therapeutic potential of neuro-glia coupling in epilepsy, 5th ICDDT Dubai, 2013
Pál I, Nyitrai G, Kardos J, Héja L: Neuronal and astroglial correlates underlying spatiotemporal intrinsic optical signal in the rat hippocampal slice, PLOS ONE 8, e57694, 2013
Nyitrai G, Keszthelyi T, Bóta A, Simon Á, Tőke O, Horváth G, Pál I, Kardos J, Héja L: Sodium selective ion channel formation in living cell membranes by polyamidoamine dendrimer, BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - BIOMEMBRANES 1828, 1873-1880, 2013
Kékesi O, Kardos J, Héja L: Astrocyte calcium dynamics reveal neuro-glia coupling during recurrent epileptiform discharge, 7th SFB35 Symposium, Transmembrane Transporters in Health and Disease, Vienna, Sept 24-25, 2014
Héja L: Astrocytic target mechanisms in epilepsy, CURRENT MEDICINAL CHEMISTRY 21, 755-763, 2014




 

Events of the project

  
2014-11-19 09:25:35
Kutatóhely váltás
A kutatás helye megváltozott. Korábbi kutatóhely: Molekuláris Farmakológiai Intézet (MTA Természettudományi Kutatóközpont), Új kutatóhely: Kognitív Idegtudományi és Pszichológiai Intézet (MTA Természettudományi Kutatóközpont).
2013-05-07 09:16:29
Résztvevők változása
2012-01-03 10:19:14
Kutatóhely váltás
A kutatás helye megváltozott. Korábbi kutatóhely: Biomolekuláris Kémiai Intézet (MTA Kémiai Kutatóközpont), Új kutatóhely: Molekuláris Farmakológiai Intézet (MTA Kémiai Kutatóközpont).



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