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.

Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases / Bruno, Stefano; Margiotta, Marilena; Pinto, Andrea; Cullia, Gregorio; Conti, Paola; De Micheli, Carlo; Mozzarelli, Andrea. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 24:12(2016), pp. 2654-2659. [10.1016/j.bmc.2016.04.033]

Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases

BRUNO, Stefano
;
MARGIOTTA, MARILENA;MOZZARELLI, Andrea
2016

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.
Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases / Bruno, Stefano; Margiotta, Marilena; Pinto, Andrea; Cullia, Gregorio; Conti, Paola; De Micheli, Carlo; Mozzarelli, Andrea. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 24:12(2016), pp. 2654-2659. [10.1016/j.bmc.2016.04.033]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2813281
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