title: Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets.
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.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom.
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Gould
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Sterk
authors.forename: Hermann
authors.initials: H
authors.lastname: Tenor
authors.forename: Stefan
authors.initials: S
authors.lastname: Kunz
authors.forename: Edith
authors.initials: E
authors.lastname: Luginbuehl
authors.forename: Thomas
authors.initials: T
authors.lastname: Seebeck
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: C000611990:NPD-001; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D013777:Tetrazoles; D010727:Phosphoric Diester Hydrolases