title: Hypervalent organotellurium compounds as inhibitors of P. falciparum calcium-dependent cysteine proteases.
abstract: Hypervalent organotellurium compounds (organotelluranes) have shown several promising applications, including their use as potent and selective cysteine protease inhibitors and antiprotozoal agents. Here, we report the antimalarial activities of three organotellurane derivatives (RF05, RF07 and RF19) in two Plasmodium falciparum strains (CQS 3D7 and CQR W2), which demonstrated significant decreases in parasitemia in vitro. The inhibition of intracellular P. falciparum proteases by RF05, RF07 and RF19 was determined and the IC50 values were 3.7±1.0μM, 1.1±0.2μM and 0.2±0.01μM, respectively. Using an assay performed in the presence of the ER Ca(2+)-ATPase inhibitor we showed that the main enzymatic targets were cysteine proteases stimulated by calcium (calpains). None of the compounds tested caused haemolysis or a significant decrease in endothelial cell viability in the concentration range used for the inhibition assay. Taken together, the results suggest promising compounds for the development of antimalarial drugs.
authors.affiliation: Departamento de Biofisica, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors.forename: Sarah
authors.initials: S
authors.lastname: El Chamy Maluf
authors.affiliation: Departamento de Biofisica, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors.forename: Pollyana M S
authors.initials: PMS
authors.lastname: Melo
authors.affiliation: Núcleo de Pesquisa em Química Biológica, Centro de Ciências da Saúde, Universidade Federal de São João Del Rei, Divinópolis, MG, Brazil.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Varotti
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo, Santos, SP, Brazil.
authors.forename: Marcos L
authors.initials: ML
authors.lastname: Gazarini
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Rodrigo L O R
authors.initials: RLOR
authors.lastname: Cunha
authors.affiliation: Departamento de Biofisica, Universidade Federal de São Paulo, São Paulo, SP, Brazil. Electronic address: ak.carmona@unifesp.br.
authors.forename: Adriana K
authors.initials: AK
authors.lastname: Carmona
mesh_terms: D000962:Antimalarials / Q000494:pharmacology* / Q000633:toxicity; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D055808:Drug Discovery; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D013691:Tellurium / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D009942:Organometallic Compounds; D002154:Calpain; D013691:Tellurium; D002118:Calcium
keywords: Calpain; Malaria; Plasmodium; Tellurium compounds