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Calcium dependent protein kinases and Malaria: Identification of chemical start point for drug discovery
Symposium: Academic Drug Discovery: Challenges and perspectives
Imperial College London, March 2011
Oliver Billker & Katie Chapman
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Antimalarial drugs
• No longer useful against P. falciparum
• Wide spread resistance
ArtemisininChloroquine
• First-line treatment of P. falciparum
• Component of a combination.
• Reduced efficacy observed in SE Asia.
Important to develop a well supplied pipeline of new antimalarials.
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Antimalarial drug development
• Antimalarials are not economically attractive to the pharmaceutical industry.
• Public-private partnerships play a key role.
E.g. Medicines for Malaria Venture, Wellcome Trust, Bill & Melinda Gates Foundation
Opportunity and need for academic institutions to make an impact.
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A paradigm shift in antimalarial screening
Cell based screens
Libraries of >20.000starting
points for drug
development
https://www.ebi.ac.uk/chembl/
Target based
screening
Genetic tools for target identification at scale(Sanger team)
Identify mechanism of induced resistance.
Screen against validated targets
Prioritise by chemistry, IP, etc.
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2 million GSK compounds
13533 inhibitors of P. falciparum growth IC50 < 1 µM
242 inhibitors P. falciparum CDPK 1, 4 or 5
Nature, March 2010
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Systematic prioritisation of parasite kinase targets in a malaria parasite of rodents
• Gene deletion analysis of 65 protein kinases.
• Kinomes are highly conserved across Plasmodium species.
• >1/3 of parasite protein kinases are redundant in blood stages.
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Comparative analysis of Plasmodium kinomes
Different in P. falciparumRedundant in P. bergheiRita Tewari
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calmodulin-likedomain
kinase domain
Calcium dependent protein kinases (CDPKs)
• Plant-like kinases with a unique activation mechanism.
Billker & Doerig 2010
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Target selection
Redundant in P. berghei
CamK
Plant like Opportunity for selectivityFamily Opportunity for multi-target inhibitor.
CDPK1 and 5:Essential in blood stages.
CDPK1 and 4Essential for transmission.
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CDPK5
Predicted CDPK functions
CDPK1
CDPK4
CDPK1
CDPK4
CDPK1
CDPK1
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PLC
IP3
PIP2
ER
Ca2+
Ca2+
Ca2+
PLC
C D PK 4
Receptor
Xanthurenic acid Temperature
Host cell lysis
Male gamete formation
Differential gene expression
N
OH
OHCOOH
Guanlyl
cyclasecGMPPKG
Phospho-diesterases
Map-2
CDPK4 is required for male gamete formation
SRPK
PKG
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Pic
eata
nnol
Res
vera
tol
PP
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P1
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rcet
inP
urfa
lcam
ine .
RO
3188
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taur
ospo
rine ..
1-N
M P
P1
3-B
R P
P1
1-N
A P
P1
3-M
B P
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PP
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HA
665
752
Mex
iletin
e H
Cl
1/pI
C50
2
3
4
5
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7
8
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CDPK1CDPK4
Comparative profiling of recombinant PfCDPK1 and 4
unselective C1 selective C4 selective
Katie Chapman, Imperial College Drug Discovery
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cdpk4
CDPK4 is required for male gamete formation
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DMSO 1NM-PP1
DMSO Rm-1-132 1NM-PP1Ave
rage
num
ber o
f ooc
ysts
0
10
20
30
40
50
DMSO 1NM-PP1
The CDPK4 inhibitor 1NM-PP1 blocks parasite transmission to mosquitoes
Lotta Burström
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P. berghei CDPK1-GFP is expressed throughout life cycle
ookinete
gametocytes
oocyst
sporozoitesSarah Sebastian
schizont
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cdpk1 knock down blocks development…
WT ookinete
zygote ookineteretort
Sarah Sebastian
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1 20 120 0.05 2,400
2 35 275 0.09 3,000
average oocysts/midgutfeed n WT CDPK1 fold change
…and prevents transmission of P. berghei to mosquitoes
Sarah Sebastian
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Target prioritisation: CDPK5 is also essential for blood stage development.
Science 238 (2010)
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• CDPK1, 4 & 5 are individually essential for parasite development at different life cycle stages.
• Absence of redundancy due to different subcellular
localisations (lipid modification), expression patterns, substrate preferences.
• Pan-CDPK inhibitor could exploit synergies and delay emergence of resistance.
Target summary
Aim: Screen P. falciparum versions of all three targets to explore feasibility of pan-CDPK inhibition