Chemical validation of phosphodiesterase C as a chemotherapeutic target in Trypanosoma cruzi, the etiological agent of Chagas' disease.
Trypanosoma cruzi phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its N-terminal region (S. Kunz et al., FEBS J. 272:6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on T. cruzi amastigote growth, and we obtained several useful hits. We then conducted homology modeling of T. cruzi PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity in vitro, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in T. cruzi. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.
King-Keller
Sharon
S
Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, 350B Paul D. Coverdell Center, 500 D.W. Brooks Dr., Athens, GA 30602, USA.
Li
Minyong
M
Smith
Alyssa
A
Zheng
Shilong
S
Kaur
Gurpreet
G
Yang
Xiaochuan
X
Wang
Binghe
B
Docampo
Roberto
R
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy / Q000382:microbiology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology* / Q000472:pathogenicity
D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D010727:Phosphoric Diester Hydrolases