title: Falcipain-2 inhibition by suramin and suramin analogues.
abstract: Falcipain-2 is a cysteine protease of the malaria parasite Plasmodium falciparum that plays a key role in the hydrolysis of hemoglobin, a process that is required by intraerythrocytic parasites to obtain amino acids. In this work we show that the polysulfonated napthylurea suramin is capable of binding to falcipain-2, inhibiting its catalytic activity at nanomolar concentrations against both synthetic substrates and the natural substrate hemoglobin. Kinetic measurements suggest that the inhibition occurs through an noncompetitive allosteric mechanism, eliciting substrate inhibition. Smaller suramin analogues and those with substituted methyl groups also showed inhibition within the nanomolar range. Our results identify the suramin family as a potential starting point for the design of falcipain-2 inhibitor antimalarials that act through a novel inhibition mechanism.
authors.affiliation: Laboratory for Pharmaceutical Biotechnology, School of Pharmacy, Federal University of Rio de Janeiro, CCS, Bss34, Ilha do Fundão, 21941-590 Rio de Janeiro, RJ, Brazil.
authors.forename: Adriana Fonseca
authors.initials: AF
authors.lastname: Marques
authors.forename: Daniel
authors.initials: D
authors.lastname: Esser
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Luis Mauricio T R
authors.initials: LM
authors.lastname: Lima
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D013498:Suramin / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D013498:Suramin; D003546:Cysteine Endopeptidases; C416224:falcipain 2