Abstract
Due to their critical involvement in the execution of the malaria parasite developmental pattern both in the mosquito vector and in the human host, Plasmodium calcium-dependent protein kinases (CDPKs) are considered promising candidates for the development of new tools to block malaria transmission. We report here that the phenothiazine trifluoperazine non-competitively inhibits Plasmodium falciparum CDPK4 in the micromolar range while other calmodulin antagonists only marginally affect the enzyme activity, and we propose the inhibition mechanism. Our results demonstrate that selective enzyme inhibition is achievable by targeting its calmodulin-like domain. This observation could be exploited for the discovery of innovative phenothiazine-based CDPK inhibitors of potential medical interest.
Keywords: malaria, Plasmodium falciparum, protein kinases, antimalaria drug discovery, calmodulin antagonists, CDPKs, CaM-LD, Pf-HisCDPK4, TFP, Subcloning, EDTA, FPLC, AMP, Thermal melt/thermal shift assays, RFUmalaria, Plasmodium falciparum, protein kinases, antimalaria drug discovery, calmodulin antagonists, CDPKs, CaM-LD, Pf-HisCDPK4, TFP, Subcloning, EDTA, FPLC, AMP, Thermal melt/thermal shift assays, RFU
Protein & Peptide Letters
Title: The Potent Antiplasmodial Calmodulin-Antagonist Trifluoperazine Inhibits Plasmodium falciparum Calcium-Dependent Protein Kinase 4
Volume: 18 Issue: 12
Author(s): Andrea Cavagnino, Franca Rossi and Menico Rizzi
Affiliation:
Keywords: malaria, Plasmodium falciparum, protein kinases, antimalaria drug discovery, calmodulin antagonists, CDPKs, CaM-LD, Pf-HisCDPK4, TFP, Subcloning, EDTA, FPLC, AMP, Thermal melt/thermal shift assays, RFUmalaria, Plasmodium falciparum, protein kinases, antimalaria drug discovery, calmodulin antagonists, CDPKs, CaM-LD, Pf-HisCDPK4, TFP, Subcloning, EDTA, FPLC, AMP, Thermal melt/thermal shift assays, RFU
Abstract: Due to their critical involvement in the execution of the malaria parasite developmental pattern both in the mosquito vector and in the human host, Plasmodium calcium-dependent protein kinases (CDPKs) are considered promising candidates for the development of new tools to block malaria transmission. We report here that the phenothiazine trifluoperazine non-competitively inhibits Plasmodium falciparum CDPK4 in the micromolar range while other calmodulin antagonists only marginally affect the enzyme activity, and we propose the inhibition mechanism. Our results demonstrate that selective enzyme inhibition is achievable by targeting its calmodulin-like domain. This observation could be exploited for the discovery of innovative phenothiazine-based CDPK inhibitors of potential medical interest.
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Cite this article as:
Cavagnino Andrea, Rossi Franca and Rizzi Menico, The Potent Antiplasmodial Calmodulin-Antagonist Trifluoperazine Inhibits Plasmodium falciparum Calcium-Dependent Protein Kinase 4, Protein & Peptide Letters 2011; 18 (12) . https://dx.doi.org/10.2174/092986611797642742
DOI https://dx.doi.org/10.2174/092986611797642742 |
Print ISSN 0929-8665 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5305 |
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