Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness.
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.
Marine Biological Laboratory, Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Woods Hole, Massachusetts 02543, United States.
Nicholas D
ND
Bland
Cuihua
C
Wang
Craig
C
Tallman
Alden E
AE
Gustafson
Zhouxi
Z
Wang
Trent D
TD
Ashton
Stefan O
SO
Ochiana
Gregory
G
McAllister
Kristina
K
Cotter
Anna P
AP
Fang
Lara
L
Gechijian
Norman
N
Garceau
Rajiv
R
Gangurde
Ron
R
Ortenberg
Mary Jo
MJ
Ondrechen
Robert K
RK
Campbell
Michael P
MP
Pollastri
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
D001549:Benzamides; D011725:Pyridines; D011994:Recombinant Proteins; D014344:Trypanocidal Agents; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C087566:piclamilast