Premium
A novel inhibitor of the T. brucei TbPDE2 cAMP phosphodiesterase family is a potent trypanocidal agent
Author(s) -
Laxman Sunil,
Beavo Joseph A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1116-c
Subject(s) - trypanosoma brucei , activator (genetics) , in vivo , biology , phosphodiesterase , enzyme , gene knockdown , in vitro , pharmacology , biochemistry , cyclic nucleotide phosphodiesterase , gene , genetics
African sleeping sickness is caused by the protozoan parasite Trypanosoma brucei . Current chemotherapy against this protozoan is ineffective and toxic. The T. brucei TbPDE2 family of cAMP phosphodiesterases (PDEs) are essential genes for bloodstream form T. brucei , making them attractive new drug targets. Though TbPDE2s are biochemically very similar to their mammalian counterparts, they are resistant to most mammalian PDE inhibitors. This study reports a novel inhibitor (8‐pCPT‐2′‐OMe‐cAMP) of the TbPDE2 family, obtained by screening compounds known to affect other cNMP binding enzymes. The compound was found to potently inhibit the T. brucei TbPDE2 family, with a K i of ~5 μM, and was not hydrolyzed by the TbPDE2 enzymes. It showed similar affinities for recombinant as well as native enzymes, and was highly cytotoxic to trypanosomes at concentrations similar to the in vitro K i 's, preventing proliferation and causing trypanosome death in 40–72 hours. This effect mimicked the phenotype seen in RNAi mediated TbPDE2 knockdown studies in T. brucei . A similar in vitro and in vivo chemotoxic effect was seen with the PDE inhibitor Dipyridamole, also an inhibitor of the TbPDE2 enzymes. The compound identified showed selectivity for the TbPDEs over mammalian PDEs, though it is a known activator of mammalian EPACs. As the presence of cAMP activated protein kinases in trypanosomes is questionable, and no EPACs or other cAMP binding proteins have been identified in the trypanosome genome, it is likely that TbPDE2s are the targets of this compound in vivo . This data suggests the therapeutic potential of this compound (directly, or as a lead) as a trypanocidal drug, with PDEs as their primary target.