Selectivity of 3-bromo-isoxazoline inhibitors between human and Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenases |
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| Affiliation: | 1. Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 23/a, 43124 Parma, Italy;2. Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy;3. National Institute of Biostructure and Biosystems, Rome, Italy;4. Institute of Biophysics, CNR, Pisa, Italy;1. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy;2. DiSTABiF, Second University of Naples, Via Vivaldi 43, 81100 Caserta, Italy;3. Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55099 Mainz, Germany;1. Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil;2. Grupo de Química Medicinal do IQSC/USP, Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil;3. Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil;1. Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany;2. Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany;3. Biochemistry Center of Heidelberg University (BZH), Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany |
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| 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. |
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| Keywords: | Glyceraldehyde 3-phosphate dehydrogenase Covalent inhibition 3-Br-isoxazoline Plasmodium falciparum Malaria |
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