1. Phosphodiesterases as drug targets in kinetoplastid parasites

2. Kinetoplastid parasites
Trypanosoma brucei (Sleeping sickness)
Leishmania (Leishmaniasis)
Trypanosoma cruzi (Chagas disease)
microbewiki
msu.edu
centers for disease control and prevention

3. Phosphodiesterases (PDEs)
wikipedia
Kunz et al, 2006

4. Phosphodiesterases (PDEs)
Trypanosoma brucei
TbrPDEB1: Flagellum
TbrPDEB2: Cell body B2
microbewiki B1
patientimages
Luginbuehl et al, 2010

5. Phosphodiesterases (PDEs)
Trypanosoma brucei
TbrPDEB1
Jansen et al, 2013

6. Phosphodiesterases (PDEs)
Trypanosoma brucei
TbrPDEB1
Jansen et al, 2013
Jansen et al, 2013

7. Phosphodiesterases (PDEs)
Nomenclature
HsPDE4Al
Human PDE
Family 4 (cAMP-specific)
Gene A
Splice variant 1
Kunz et al, 2006

8. Phosphodiesterases (PDEs)
Humans: 11 families, class I1
Family-selective drugs
Jansen et al, 2013
Jansen et al, 2013
1Kunz et al, 2006

9. Compound A (Cpd A) Class: Tetrahydrophthalazinone
Most potent inhibitor of TbrPDEB1 and TbrPDEB2
cAMP
cAMP
cAMP
cAMP
cAMP
cAMP
macroevolution.net
De Koning et al, 2012
De Koning et al, 2012

10. Compound A (Cpd A) Cell cycle effects
Globular, multinuclear, multiflagellated
1N1K
2N2K
1N2K
>2N2K
2N2K
De Koning et al, 2012
De Koning et al, 2012

11. Compound A (Cpd A)
De Koning et al, 2012
De Koning et al, 2012

12. Compound A (Cpd A)
De Koning et al, 2012

13. Catalytic domains of leishmania major and human PDEs
LmjPDEB1 (green)
Human PDE4D (gold, blue)
IBMX (3-isobutyl-1-methylxanthine)
Seebeck et al, 2011

14. Thank you for your attention!

15. List of literature
De Koning H. P., Gould M. K., Sterk G. J., Tenor H., Kunz S., Luginbuehl E., and Seebeck T Pharmacological validation of trypanosoma brucei phosphodiesterases as novel drug targets. The Journal of Infectious Diseases, 206: 229 – 37.
Jansen C., Wang H., Kooistra A. J., de Graaf C., Orrling K., Tenor H., Seebeck T., Bailey D., de Esch I. J. P., Ke H., and Leurs R Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. J Med Chem, 56: doi: /jm
Johner A., Kunz A., Linder M., Shakur Y., and Seebeck T Cyclic nucleotide specific phosphodiesterases of Leishmania major. BMC Microbiol. 6: 25
Kunz S., Beavo J. A., D’Angelo M. A., Flawia M. M., Francis S. H., Johner A., Laxman S., Oberholzer M., Rascon A., Shakur Y., Wentzinger L., Zoraghi R., and Seebeck T Cyclic nucleotide specific phosphodiesterases of the kinetoplastida: a unified nomenclature. Mol Biochem Parasitol, 145: 133 – 5.
Luginbuehl E., Ryter D., Schranz-Zumkehr J., Oberholzer M., Kunz S., and Seebeck T The N terminus of phosphodiesterase TbrPDEB1 of trypanosoma brucei contains the signal for integration into the flagellar skeleton. Eukaryot Cell, 9: 1466 – doi: /EC
Malki-Feldman L. and Jaffe C.L Leishmania major: effect of protein kinase A and phosphodiesterase activity on infectivity and proliferation of promastigotes. Exp Parasitol, 123: doi: /j.exppara
Seebeck T., Sterk G. J., and Ke H Phosphodiesterase inhibitors as a new generation of antiprotozoan drugs: exploiting the benefit of enzymes that are highly conserved between host and parasite. NIH, 3: doi: /fmc

16. Register of illustrations
De Koning H. P., Gould M. K., Sterk G. J., Tenor H., Kunz S., Luginbuehl E., and Seebeck T Pharmacological validation of trypanosoma brucei phosphodiesterases as novel drug targets. The Journal of Infectious Diseases, 206: 229 – 37.
Jansen C., Wang H., Kooistra A. J., de Graaf C., Orrling K., Tenor H., Seebeck T., Bailey D., de Esch I. J. P., Ke H., and Leurs R Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure. J Med Chem, 56: doi: /jm
Kunz S., Beavo J. A., D’Angelo M. A., Flawia M. M., Francis S. H., Johner A., Laxman S., Oberholzer M., Rascon A., Shakur Y., Wentzinger L., Zoraghi R., and Seebeck T Cyclic nucleotide specific phosphodiesterases of the kinetoplastida: a unified nomenclature. Mol Biochem Parasitol, 145: 133 – 5.
Seebeck T., Sterk G. J., and Ke H Phosphodiesterase inhibitors as a new generation of antiprotozoan drugs: exploiting the benefit of enzymes that are highly conserved between host and parasite. NIH, 3: doi: /fmc