2. Academic Validation
  3. Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness

Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness

  • J Med Chem. 2011 Dec 8;54(23):8188-94. doi: 10.1021/jm201148s.
Nicholas D Bland 1,  Cuihua Wang,  Craig Tallman,  Alden E Gustafson,  Zhouxi Wang,  Trent D Ashton,  Stefan O Ochiana,  Gregory McAllister,  Kristina Cotter,  Anna P Fang,  Lara Gechijian,  Norman Garceau,  Rajiv Gangurde,  Ron Ortenberg,  Mary Jo Ondrechen,  Robert K Campbell,  Michael P Pollastri
Affiliations

Affiliation

  • 1 Marine Biological Laboratory, Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Woods Hole, Massachusetts 02543, United States.
PMID: 22023548 DOI: 10.1021/jm201148s
Abstract

Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) Enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei , the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 Inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei . We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human Enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any Other human PDEs.

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