Biology Reference
In-Depth Information
Therapeutic Potential of Phosphodiesterase
Inhibitors in Parasitic Diseases
Yasmin Shakur, Harry P. de Koning, Hengming Ke, Junichi Kambayashi,
and Thomas Seebeck
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
1.1 Kinetoplastida: Life Cycle and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
1.2 Therapies Currently in Clinical Use or in Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
1.3 Cyclic Nucleotide Signaling in the Kinetoplastid Parasites . . . . . . . . . . . . . . . . . . . . . . . . . 492
2 Kinetoplastid Phosphodiesterases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
2.1 Primary Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
2.2 Biological Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
3 The Promise and the Challenge of Targeting PDEs for Treatment
of the Kinetoplastid Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.1 Therapeutic Potential of Kinetoplastid PDE Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
3.2 Crystal Structure of
Leishmania major
Phosphodiesterase B1 and Implications
for Selectivity of Parasite PDE Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
3.3 Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
4 Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
Abstract Protozoan parasites of the order kinetoplastida are the causative agents
of three of the world's most important neglected human diseases: African trypano-
somiasis, American trypanosomiasis, and leishmaniasis. Current therapies are
limited, with some treatments having serious and sometimes lethal side effects.
Y. Shakur (
) and J. Kambayashi
Otsuka Maryland Medicinal Laboratories Inc, 9900 Medical Center Drive, Rockville, MD 20850,
USA
e-mail: yasminshakur@ymail.co
H.P. de Koning
Institute of Biomedical and Life Sciences, Glasgow Biomedical Research Centre, University of
Glasgow, Glasgow G12 8TA, UK
H. Ke
Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC
27599-260, USA
T. Seebeck
Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland
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