TY - JOUR T1 - Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1364 LP - 1372 DO - 10.1124/mol.62.6.1364 VL - 62 IS - 6 AU - Paul R. Graves AU - Jesse J. Kwiek AU - Patrick Fadden AU - Rupa Ray AU - Klaas Hardeman AU - Andrew M. Coley AU - Michael Foley AU - Timothy A. J. Haystead Y1 - 2002/12/01 UR - http://molpharm.aspetjournals.org/content/62/6/1364.abstract N2 - The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear. In this study, we used a functional proteomics approach that exploited the structural similarities between the quinoline compounds and the purine ring of ATP to identify quinoline-binding proteins. Several quinoline drugs were screened by displacement affinity chromatography against the purine binding proteome captured with γ-phosphate-linked ATP-Sepharose. Screening of the human red blood cell purine binding proteome identified two human proteins, aldehyde dehydrogenase 1 (ALDH1) and quinone reductase 2 (QR2). In contrast, no proteins were detected upon screening of thePlasmodium falciparum purine binding proteome with the quinolines. In a complementary approach, we passed cell lysates from mice, red blood cells, or P. falciparum over hydroxychloroquine- or primaquine-Sepharose. Consistent with the displacement affinity chromatography screen, ALDH and QR2 were the only proteins recovered from mice and human red blood cell lysate and no proteins were recovered from P. falciparum. Furthermore, the activity of QR2 was potently inhibited by several of the quinolines in vitro. Our results show that ALDH1 and QR2 are selective targets of the quinolines and may provide new insights into the mechanism of action of these drugs. ER -