Title
Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma Cruzi, the Etiological Agent of Chagas' Disease
Funding Source
Georgia Research Alliance Collaboration, National Institutes of Health
Grant Number
AI-068647, AI-082542, AI-060546
Department
Department of Chemistry
Document Type
Article
Publication Date
9-2010
Abstract
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.
Recommended Citation
King-Keller, S.; Lee, M.; Smith, A.; Zheng, Shilong; Kaur, G.; Yang, X.; Wang, B.; and DeCampo, R., "Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma Cruzi, the Etiological Agent of Chagas' Disease" (2010). Faculty and Staff Publications. 164.
https://digitalcommons.xula.edu/fac_pub/164
Comments
DOI: 10.1128/AAC.00313-1
PubMed ID: 20625148
American Society for Microbiology: Open Access Policy
ACKNOWLEDGMENTS
We thank Thomas Seebeck (University of Bern, Bern, Switzerland) for the PDE-deficient S. cerevisiae strain PP5 transformed with the construct containing the entire full-length open reading frame of TcrPDEC, Melina Galizzi for technical help, and Alejandra Schoijet and Guillermo Alonso (University of Buenos Aires, Buenos Aires, Argentina) for PDE activity protocols. We also thank OpenEye Scientific Software for the use of the FRED, FILTER, and QuACPAC programs and Breadth Technology for the use of the IDEA package.
This work was supported by a Georgia Research Alliance Collaboration Planning Grant (to R.D. and B.W.) and by NIH grants AI-068647 and AI-082542 (to R.D.). S.K.-K. was supported by NIH training grant AI-060546 to the Center for Tropical and Emerging Global Diseases.