Document 6569402

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]