Discovery of Covalent Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase, A Target for the Treatment of Malaria

• Published in: Journal of medicinal chemistry Vol. 57; no. 17; pp. 7465 - 7471
• Main Authors: Bruno, Stefano, Pinto, Andrea, Paredi, Gianluca, Tamborini, Lucia, De Micheli, Carlo, La Pietra, Valeria, Marinelli, Luciana, Novellino, Ettore, Conti, Paola, Mozzarelli, Andrea
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-09-2014
• Subjects: Animals; Biocatalysis - drug effects; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glyceraldehyde-3-Phosphate Dehydrogenases - antagonists & inhibitors; Glyceraldehyde-3-Phosphate Dehydrogenases - chemistry; Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism; Humans; Isoxazoles - chemical synthesis; Isoxazoles - chemistry; Isoxazoles - pharmacology; Kinetics; Malaria, Falciparum - drug therapy; Malaria, Falciparum - parasitology; Models, Chemical; Models, Molecular; Molecular Structure; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium falciparum - physiology; Protein Binding; Protein Structure, Tertiary; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - chemistry; Protozoan Proteins - metabolism; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrophotometry; Static Electricity; Time Factors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500747h

We developed a new class of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase, a validated target for the treatment of malaria, by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalent, selective bond to the catalytic cysteine, as demonstrated by mass spectrometry. Substituents on the isoxazolinic ring modulated the potency up to 20-fold, predominantly due to an electrostatic effect, as assessed by computational analysis.