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Calcium dependent protein kinases and Malaria: Identification of chemical start point for drug discovery. Oliver Billker & Katie Chapman. Symposium: Academic Drug Discovery: Challenges and perspectives Imperial College London, March 2011. Antimalarial drugs. Artemisinin. C hloroquine.

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Symposium academic drug discovery challenges and perspectives

Calcium dependent protein kinases and Malaria: Identification of chemical start point for drug discovery

Oliver Billker & Katie Chapman

Symposium: Academic Drug Discovery: Challenges and perspectives

Imperial College London, March 2011


Antimalarial drugs

Antimalarial drugs

Artemisinin

Chloroquine

  • First-line treatment of P. falciparum

  • Component of a combination.

  • Reduced efficacy observed in SE Asia.

  • No longer useful against P. falciparum

  • Wide spread resistance

Important to develop a well supplied pipeline of new antimalarials.


Antimalarial drug development

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.


A paradigm shift in antimalarial screening

A paradigm shift in antimalarial screening

Prioritise by chemistry, IP, etc.

Target basedscreening

Libraries of >20.000

starting points for drug development

Identify mechanism of induced resistance.

Cell based

screens

Screen against validated targets

Genetic tools for target identification at scale

(Sanger team)

https://www.ebi.ac.uk/chembl/


Symposium academic drug discovery challenges and perspectives

Nature, March 2010

13533 inhibitors of P. falciparum growth IC50 < 1 µM

242 inhibitorsP. falciparum CDPK 1, 4 or 5

2 million GSK compounds


Systematic prioritisation of parasite kinase targets in a malaria parasite of rodents

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.


Comparative analysis of plasmodium kinomes

Comparative analysis of Plasmodium kinomes

Redundant in P. berghei

Different in P. falciparum

Rita Tewari


Symposium academic drug discovery challenges and perspectives

  • Calcium dependent protein kinases (CDPKs)

  • Plant-like kinases with a unique activation mechanism.

calmodulin-likedomain

kinase domain

Billker & Doerig 2010


Symposium academic drug discovery challenges and perspectives

Target selection

Plant like  Opportunity for selectivity

Family  Opportunity for multi-target inhibitor.

CamK

CDPK1 and 5:

Essential in blood stages.

CDPK1 and 4

Essential for transmission.

Redundant in P. berghei


Symposium academic drug discovery challenges and perspectives

Predicted CDPK functions

CDPK4

CDPK1

CDPK1

CDPK5

CDPK1

CDPK4

CDPK1


Cdpk4 is required for male gamete formation

CDPK4 is required for male gamete formation

Guanlyl cyclase

PKG

Phospho-diesterases

cGMP

PKG

SRPK

Map-2

Differential gene expression

Male gamete formation

Host cell lysis


Symposium academic drug discovery challenges and perspectives

Comparative profiling of recombinant PfCDPK1 and 4

unselective

C1 selective

C4 selective

Katie Chapman, Imperial College Drug Discovery


Cdpk4 is required for male gamete formation1

CDPK4 is required for male gamete formation

cdpk4


Symposium academic drug discovery challenges and perspectives

The CDPK4 inhibitor 1NM-PP1 blocks parasite transmission to mosquitoes

DMSO 1NM-PP1

DMSO

1NM-PP1

Lotta Burström


Symposium academic drug discovery challenges and perspectives

P. berghei CDPK1-GFP is expressed throughout life cycle

schizont

ookinete

oocyst

gametocytes

sporozoites

Sarah Sebastian


Symposium academic drug discovery challenges and perspectives

cdpk1 knock down blocks development…

ookinete

zygote

retort

WT ookinete

Sarah Sebastian


Symposium academic drug discovery challenges and perspectives

…and prevents transmission of P. berghei to mosquitoes

average oocysts/midgut

feed n WT CDPK1 fold change

1 20 120 0.05 2,400

2 35 275 0.09 3,000

Sarah Sebastian


Symposium academic drug discovery challenges and perspectives

Target prioritisation: CDPK5 is also essential for blood stage development.

Science 238 (2010)


Symposium academic drug discovery challenges and perspectives

Target summary

  • 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.

Aim: Screen P. falciparum versions of all three targets to explore feasibility of pan-CDPK inhibition


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