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 / S. Bruno, M. Margiotta, A. Pinto, G. Cullia, P. Conti, C. De Micheli, A. Mozzarelli. - 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

A. Pinto;G. Cullia;P. Conti;C. De Micheli
Penultimo
;
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.
3-Br-isoxazoline; covalent inhibition; glyceraldehyde 3-phosphate dehydrogenase; malaria; plasmodium falciparum; biochemistry; clinical biochemistry; molecular biology; molecular medicine; organic chemistry; drug discovery3003 pharmaceutical science; 3003
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/10 - Biochimica
2016
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/454770
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