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Laboratory for Structural Biology of GPCRs GPCR Network – Russia GPCR Biology Team GPCR Targets Receptor subfamily Vision rhodopsin CNS, Pain acetylcholine, dopamine, serotonin, opioid, cannabinoid, etc Function Diseases Drugs Companies Leukotriene (lipid) Chemotaxis, inflammation and immune response Asthma, allergies, atherosclerosis and other cardiovascular diseases Zafirlukast, Montelukast + 3 drugs in clinical trials Astra Zeneca, Merck, Johnson & Johnson, Cellceutix, Dong Wha Endothelin (peptide) Vasoconstriction regulation and inflammation ABCD syndrome and Waardenburg syndrome, cardiovascular disease and cancer. Letairis, Tracleer, Pfizer, Sitxentan + 7 AstraZeneca, drugs in clinical BMS, Abbott trials Urotensin-II (peptide) Constriction of vessels and muscles Cardiovascular diseases, hypertension, atherosclerosis, renal disease Drug leads: Palosuran, BIM-23127, SB-611812 Galanin receptor Galanin (peptide) Regulation of pain, appetite, insulin, memory, learning and reproduction Alzheimer's disease, depression, epilepsy, alcoholism and addiction to drugs. Galnon, Galmic + several drugs Synapticin clinical trials Lundbeck and development GABAB receptor GABA (small moleculeRegulation of neuromuscle tone transmitter) Pain, depression, alcoholism and drug addiction. Baclofen, Profolol, Phenibut, GHB + 4 drugs in clinical trials Leukotriene receptors Cardiovascular adrenergic, adenosine, purinergic, angiotensin, etc CysLT1, CysLT2, Allergy histamine Immune System, HIV, Cancer cytokine, sphingosine Native Ligand Vadim Cherezov Nelli Khabibulina Mikhail Shevtsov Aleksandra Luginina Head of the Laboratory TSRI, USA Deputy head Cell-free expression Postoctoral Fellow Urotensin receptor Graduate Student Leukotriene receptors GPR17 Endothelin receptors Metabolic parathyroid, THS, calcitonin, glucagon etc. ETA ETB GPCR Signaling Alexei Mishin Anastasia Gusach Anton Potapenko Andrii Ishchenko Graduate student Endothelin receptors Undergraduate student Leukotriene receptors Undergraduate student Endothelin receptors TSRI, USA GPCR crystallization Sergei Grudinin INRIA, France Computer modeling methods Vsevolod Katritch TSRI, USA GPCR modeling Wei Liu Ray Stevens TSRI, USA GPCR purification and crystallization Director, Bridge@USC Director, iHuman Head of GPCR Network Eveline Edelweiss IBS, France GPCR expression International Collaborations GPCRs are Targets of many Drugs • • • • Russia Both agonists & antagonists Actelion, Johnson & Johnson, GSK Addex, AstraZeneca, XenoPort, AGI Therapeutics Therapeutic Areas: Current GPCR Drugs: ~40% of all prescribed drugs Urotensin-II receptor Cardiovascular Diseases Inflammation Cancer Alcoholism and Drug Addiction Mos cow USA GPCRs (2%) make >25% of all established clinical targets China Sa n Di ego Sha nghai GPCR Structure Determination Pipeline SIDE EFFECTS First Results ETb1 receptor Crystal Structures High Throughput Screening (HTS)/ Structure Activity Relationship (SAR) 10-15 years $ 1.5 bln Gene constructions of the ETb1 were made and expressed with the help of the baculovirus expression system. The protein was tested for its homogenity thermal stability. Structure-Based Drug Design (SBDD) MIPT graduate students Alexey Mishin and Aleksandra Luginina were fully trained at the GPCR Network center in La Jolla, USA The LCP FRAP-HT analysis was performed: mobile fraction of receptor in LCP ~7-12 years <$ 1 bln GPCR Timeline Unique Research Platforms CysLT1 receptor 2014 2014 2013 2013 2012 S1P1, Opioid, mGlu1, P2Y12, mGlu5, GPR40 SMO, GCGR, CRF1 2012 CCR5, 5HT1B, 5HT2B Muscarinic, NTSR1, PAR1 2011 Histamine H1 2011 2010 2010 2009 2008 2008 2007 2007 Dopamine D 3 Chemokine CXCR4 Adenosine A2A β 1-Adrenergic 26 22 16 7 6 4 2 β 2-Adrenergic 2005 2004 2003 2002 2001 2000 2000 Rhodopsin GPCR Timeline 2006 CysLT1 gene constructions were made, virus with CysLT1 gene was achieved and titered. All constructs expression was shown CysLT1 thermal stability and monodispersity were analyzed by SEC and Thermal Shift Assay methods Contact us 1 Vadim Cherezov: [email protected] Alexei Mishin: [email protected]
