title: Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana.
abstract: Cysteine proteinases (cathepsins) from Leishmania spp. are promising molecular targets against leishmaniasis. Leishmania mexicana cathepsin L is essential in the parasite life cycle and a pivotal in virulence factor in mammals. Natural products that have been shown to display antileishmanial activity were screened as part of our ongoing efforts to design inhibitors against the L. mexicana cathepsin L-like rCPB2.8. Among them, agathisflavone (1), tetrahydrorobustaflavone (2), 3-oxo-urs-12-en-28-oic acid (3), and quercetin (4) showed significant inhibitory activity on rCPB2.8 with IC50 values ranging from 0.43 to 18.03 µM. The mechanisms of inhibition for compounds 1-3, which showed Ki values in the low micromolar range (Ki = 0.14-1.26 µM), were determined. The biflavone 1 and the triterpene 3 are partially noncompetitive inhibitors, whereas biflavanone 2 is an uncompetitive inhibitor. The mechanism of action established for these leishmanicidal natural products provides a new outlook in the search for drugs against Leishmania.
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Washington Luís Km 235, São Carlos, SP 13565-905, Brazil; Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
authors.forename: Lorena R F
authors.initials: LR
authors.lastname: de Sousa
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Washington Luís Km 235, São Carlos, SP 13565-905, Brazil.
authors.forename: Liliane
authors.initials: L
authors.lastname: Nebo
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Washington Luís Km 235, São Carlos, SP 13565-905, Brazil.
authors.forename: João B
authors.initials: JB
authors.lastname: Fernandes
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Washington Luís Km 235, São Carlos, SP 13565-905, Brazil.
authors.forename: Maria F das G F
authors.initials: MF
authors.lastname: da Silva
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Kiefer
authors.affiliation: Institute of Pharmacy and Biochemistry, Johannes Gutenberg-University Mainz, Staudinger Weg 5, D-55128 Mainz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.affiliation: Department of Chemistry, Federal University of São Carlos, Washington Luís Km 235, São Carlos, SP 13565-905, Brazil. Electronic address: dpcv@ufscar.br.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Vieira
mesh_terms: D044946:Biflavonoids / Q000494:pharmacology; D001688:Biological Products / Q000494:pharmacology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000235:genetics; D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D007894:Leishmania mexicana / Q000201:enzymology* / Q000235:genetics; D011794:Quercetin / Q000494:pharmacology; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics
chemical_list: D044946:Biflavonoids; D001688:Biological Products; D011994:Recombinant Proteins; C079168:agathisflavone; D011794:Quercetin; D002401:Cathepsin B; D056668:Cathepsin L
keywords: Biflavonoid; Cathepsin L; Leishmania mexicana; Triterpene; rCPB2.8