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

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• 作者：Stefano Bruno^a ; ^&dagger ; ; ^{stefano.bruno@unipr.it" class="auth_mail" title="E-mail the corresponding author} ; Marilena Margiotta^a ; ^&dagger ; ; Andrea Pinto^b ; Gregorio Cullia^b ; Paola Conti^b ; Carlo De Micheli^b ; Andrea Mozzarelli^a ; ^c ; ^d
• 关键词：Glyceraldehyde 3-phosphate dehydrogenase ; Covalent inhibition ; 3-Br-isoxazoline ; Plasmodium falciparum ; Malaria
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：24
• 期：12
• 页码：2654-2659
• 全文大小：460 K

文摘

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.