Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases. Issue 12 (15th June 2016)

• Record Type: Journal Article
• Authors: Bruno, Stefano; Margiotta, Marilena; Pinto, Andrea; Cullia, Gregorio; Conti, Paola; De Micheli, Carlo; Mozzarelli, Andrea
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 12(2016)
• Page Start: 2654
• Page End: 2659
• Publication Date: 2016-06-15
• Subjects: Glyceraldehyde 3-phosphate dehydrogenase -- Covalent inhibition -- 3-Br-isoxazoline -- Plasmodium falciparum -- Malaria; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.04.033
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.