gsk-256066 and Trypanosomiasis--African

Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Aminoquinolines; Binding Sites; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Repositioning; Humans; Molecular Docking Simulation; Neglected Diseases; Phosphodiesterase 4 Inhibitors; Protein Structure, Tertiary; Protozoan Proteins; Quinolines; Structure-Activity Relationship; Sulfones; Trypanosoma brucei brucei; Trypanosomiasis, African

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.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Benzamides; Catalytic Domain; Humans; Models, Molecular; Molecular Structure; Pyridines; Recombinant Proteins; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African