title: BDA-410: a novel synthetic calpain inhibitor active against blood stage malaria.
abstract: Falcipains, the papain-family cysteine proteases of the Plasmodium falciparum, are potential drug targets for malaria parasite. Pharmacological inhibition of falcipains can block the hydrolysis of hemoglobin, parasite development, and egress, suggesting that falcipains play a key role at the blood stage of parasite life cycle. In the present study, we evaluated the anti-malarial effects of BDA-410, a novel cysteine protease inhibitor as a potential anti-malarial drug. Recombinant falcipain (MBP-FP-2B) and P. falciparum trophozoite extract containing native falcipains were used for enzyme inhibition studies in vitro. The effect of BDA-410 on the malaria parasite development in vitro as well as its anti-malarial activity in vivo was evaluated using the Plasmodium chabaudi infection rodent model. The 50% inhibitory concentrations of BDA-410 were determined to be 628 and 534nM for recombinant falcipain-2B and parasite extract, respectively. BDA-410 inhibited the malaria parasite growth in vitro with an IC(50) value of 173nM causing irreversible damage to the intracellular parasite. In vivo, the BDA-410 delayed the progression of malaria infection significantly using a mouse model of malaria pathogenesis. The characterization of BDA-410 as a potent inhibitor of P. falciparum cysteine proteases, and the demonstration of its efficacy in blocking parasite growth both in vitro and in vivo assays identifies BDA-410 is an important lead compound for the development of novel anti-malarial drugs.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Li
authors.forename: Huiqing
authors.initials: H
authors.lastname: Chen
authors.forename: Jong-Jin
authors.initials: JJ
authors.lastname: Jeong
authors.forename: Athar H
authors.initials: AH
authors.lastname: Chishti
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D021261:Parasitic Sensitivity Tests; D016788:Plasmodium chabaudi / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D002154:Calpain