title: Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum.
abstract: Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5 ± 0.8 µM, 9.5 ± 0.2 µM and 4.9 ± 1.3 µM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.
authors: Centro de Biologia Molecular Estrutural (CEBIME) and.
authors: Jean Borges
authors: JB
authors: Bertoldo
authors: Louise Domeneghini
authors: LD
authors: Chiaradia-Delatorre
authors: Alessandra
authors: A
authors: Mascarello
authors: Paulo César
authors: PC
authors: Leal
authors: Marlon Norberto Sechini
authors: MN
authors: Cordeiro
authors: Ricardo José
authors: RJ
authors: Nunes
authors: Emir Salas
authors: ES
authors: Sarduy
authors: Philip Jon
authors: PJ
authors: Rosenthal
authors: Hernán
authors: H
authors: Terenzi
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods*; D004926:Escherichia coli / Q000235:genetics; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D054852:Small Molecule Libraries / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D054852:Small Molecule Libraries; D003546:Cysteine Endopeptidases; C416224:falcipain 2
keywords: Chalcones; Plasmodium falciparum; falcipain-2 inhibitors; malaria