ArticleThe Journal of biological chemistry2012
Biological and structural characterization of Trypanosoma cruzi phosphodiesterase C and Implications for design of parasite selective inhibitors.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 31 citations in OpenAlex.
- To Target or Not to TargetInternational journal of molecular sciences · 2023Article
- Evaluation of Modulators of cAMP-Response in Terms of Their Impact on Cell Cycle and Mitochondrial Activity ofFrontiers in pharmacology · 2020Article
- Methods to Investigate Signal Transduction Pathways in Trypanosoma cruzi: Cyclic Nucleotide Phosphodiesterases Assay Protocols.Methods in molecular biology (Clifton, N.J.) · 2020Article
- Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.Journal of medicinal chemistry · 2018Article
- The single cyclic nucleotide-specific phosphodiesterase of the intestinal parasite Giardia lamblia represents a potential drug target.PLoS neglected tropical diseases · 2017Article
- The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations.Molecules (Basel, Switzerland) · 2016Review
- Characterization of parasite-specific indels and their proposed relevance for selective anthelminthic drug targeting.Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases · 2016Article
- Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.Molecular pharmacology · 2015Article
- cAMP signalling in trypanosomatids: role in pathogenesis and as a drug target.Trends in parasitology · 2015Review
- Down regulation of NO signaling in Trypanosoma cruzi upon parasite-extracellular matrix interaction: changes in protein modification by nitrosylation and nitration.PLoS neglected tropical diseases · 2015Article
- New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource.Scientific reports · 2015Article
- Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning.PloS one · 2015Article
- The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference!Frontiers in pharmacology · 2015Review
- Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure.Journal of medicinal chemistry · 2013Article
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8 authors at 5 institutions in 3 countries.
Funding
Abstract
Trypanosoma cruzi phosphodiesterase C (TcrPDEC) is a potential new drug target for the treatment of Chagas disease but has not been well studied. This study reports the enzymatic properties of various kinetoplastid PDECs and the crystal structures of the unliganded TcrPDEC1 catalytic domain and its complex with an inhibitor. Mutations of PDEC during the course of evolution led to inactivation of PDEC in Trypanosoma brucei/Trypanosoma evansi/Trypanosoma congolense, whereas the enzyme is active in all other kinetoplastids. The TcrPDEC1 catalytic domain hydrolyzes both cAMP and cGMP with a K(m) of 23.8 μm and a k(cat) of 31 s(-1) for cAMP and a K(m) of 99.1 μm and a k(cat) of 17 s(-1) for cGMP, thus confirming its dual specificity. The crystal structures show that the N-terminal fragment wraps around the TcrPDEC catalytic domain and may thus regulate its enzymatic activity via direct interactions with the active site residues. A PDE5 selective inhibitor that has an IC(50) of 230 nm for TcrPDEC1 binds to TcrPDEC1 in an orientation opposite to that of sildenafil. This observation, together with the screen of the inhibitory potency of human PDE inhibitors against TcrPDEC, implies that the scaffold of some human PDE inhibitors might be used as the starting model for design of parasite PDE inhibitors. The structural study also identified a unique parasite pocket that neighbors the active site and may thus be valuable for the design of parasite-specific inhibitors.
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