Synthetic compounds from an in house library as inhibitors of falcipain-2 from Plasmodium falciparum.
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.
['Bertoldo|Jean Borges|JB|', 'Chiaradia-Delatorre|Louise Domeneghini|LD|', 'Mascarello|Alessandra|A|', 'Leal|Paulo César|PC|', 'Cordeiro|Marlon Norberto Sechini|MN|', 'Nunes|Ricardo José|RJ|', 'Sarduy|Emir Salas|ES|', 'Rosenthal|Philip Jon|PJ|', 'Terenzi|Hernán|H|']
D000962:Antimalarials D003546:Cysteine Endopeptidases D015853:Cysteine Proteinase Inhibitors D055808:Drug Discovery D004926:Escherichia coli D015394:Molecular Structure D010963:Plasmodium falciparum D054852:Small Molecule Libraries D013050:Spectrometry, Fluorescence D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Plasmodium falciparum malaria Chalcones falcipain-2 inhibitors