Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets

De Koning, H.P. , Gould, M.K., Sterk, G.J., Tenor, H., Kunz, S., Luginbuehl, E. and Seebeck, T. (2012) Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets. Journal of Infectious Diseases, 206(2), pp. 229-237. (doi: 10.1093/infdis/jir857)

Abstract

The development of drugs for neglected infectious diseases often uses parasite-specific enzymes as targets. We here demonstrate that parasite enzymes with highly conserved human homologs may represent a promising reservoir of new potential drug targets. The cyclic nucleotide-specific phosphodiesterases (PDEs) of Trypanosoma brucei, causative agent of the fatal human sleeping sickness, are essential for the parasite. The highly conserved human homologs are well-established drug targets. We here describe what is to our knowledge the first pharmacological validation of trypanosomal PDEs as drug targets. High-throughput screening of a proprietary compound library identified a number of potent hits. One compound, the tetrahydrophthalazinone compound A (Cpd A), was further characterized. It causes a dramatic increase of intracellular cyclic adenosine monophosphate (cAMP). Short-term cell viability is not affected, but cell proliferation is inhibited immediately, and cell death occurs within 3 days. Cpd A prevents cytokinesis, resulting in multinucleated, multiflagellated cells that eventually lyse. These observations pharmacologically validate the highly conserved trypanosomal PDEs as potential drug targets.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: De Koning, Professor Harry
• Authors: De Koning, H.P., Gould, M.K., Sterk, G.J., Tenor, H., Kunz, S., Luginbuehl, E., and Seebeck, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Infectious Diseases
• ISSN: 0022-1899