Inhibition of Parasite Protein Kinase C by New Antileishmanial Imidazolidin-2-one Compounds

Abstract

The protein kinase C (PKC) family of isoenzymes mediate a wide range of signal transduction pathways in many different cells lines. Little is known regarding the presence and functional roles of PKC in Leishmania spp. Here we report the inhibition of parasite PKC by new imidazolidinone compounds. The most active derivative 7 showed an important activity (IC50 = 9.9 microM) against the clinical relevant stage of parasites in comparison with Glucantime (IC50 = 464.5 microM), without inducing toxicity on human fibroblast cells (IC50 = 102 microM). Pretreatment of intact parasites with 10 microM of compound 7 inhibited 80% of PKC activity. At the same concentration, this compound inhibited 70% of the parasite-host cell invasion process. An in vivo model showed that compound 7 reduced the liver parasite burden by 25% and spleen parasite burden by 44%. These results provide the first evidence that PKC plays a critical role in the invasion process. Thus Leishmania PKC activity could be a relevant therapeutic target and the imidazolidinones novel antileishmanial candidates.

Kinetoplastid AGC Kinases

“…Although in trypanosomatids no gene orthologous to PKC has been identified [4], PKC-like activities have been described by several groups [6][7][8][9][10][11][12][13][14][15][16][17][18]. Hypothesized roles of PKC-like activity in T. cruzi are regulation of membrane transporters [11] or involvement in metacyclogenesis [9,18].…”

“…The trypanosomatid genome harbors a gene homologous to PDK-1 (Tb927.9.4910), which suggests a conservation of this mechanism. Whereas genes homologous to PKA, PKB, NDR and RSK (90 kDa ribosomal S6 kinase) kinases were identified in a previous bioinformatic survey of the kinetoplastid genomes [4], the large PKC subfamily is virtually absent in spite of numerous earlier reports of PKC-like activity [6][7][8][9][10][11][12][13][14][15][16][17][18]. The other AGC kinases identified in trypanosomatids by Parsons et al [4] do not seem to have orthologs in other organisms, and few of them have been analyzed to date.…”

Development of new antileishmanial drugs – current knowledge and future prospects

“…Included among the potential inhibitors of CRK3 cyclin-dependent kinase of Leishmania, indirubin derivatives exhibited growth arrest and change in the DNA content [104]. Evidence that PKC plays a critical role in the invasion process is highlighted by a study demonstrating that pre-treatment of intact parasites by imidazolidinone compounds inhibited PKC activity and the parasitehost cell invasion process [105].…”

Leishmania-Host Interplay: The Everlasting Rivalry

“…A new class of PKC inhibitors (imidazolidinone compounds) was shown to present great activity against amastigotes in comparison with the antimoniate glucantime. Parasite burden in liver and spleen were reduced with imidazolidinone administration, suggesting that parasite PKC may also constitute a putative therapeutic target [8].…”