title: Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases.
abstract: Compounds based on the 3-Br-isoxazoline scaffold fully inhibit glyceraldehyde 3-phosphate dehydrogenase from Plasmodium falciparum by selectively alkylating all four catalytic cysteines of the tetramer. Here, we show that, under the same experimental conditions that led to a fast and complete inhibition of the protozoan enzyme, the human ortholog was only 25% inhibited, with the alkylation of a single catalytic cysteine within the tetramer. The partial alkylation seems to produce a slow conformational rearrangement that severely limits the accessibility of the remaining active sites to bulky 3-Br-isoxazoline derivatives, but not to the substrate or smaller alkylating agents.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 23/a, 43124 Parma, Italy. Electronic address: stefano.bruno@unipr.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bruno
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 23/a, 43124 Parma, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Margiotta
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Cullia
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 23/a, 43124 Parma, Italy; National Institute of Biostructure and Biosystems, Rome, Italy; Institute of Biophysics, CNR, Pisa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054879:Halogenation; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases
keywords: 3-Br-isoxazoline; Covalent inhibition; Glyceraldehyde 3-phosphate dehydrogenase; Malaria; Plasmodium falciparum