Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome

@article{citeulike:2191724, abstract = {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 [gamma]-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 the Plasmodium 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. 10.1124/mol.62.6.1364}, author = {Graves, Paul R. and Kwiek, Jesse J. and Fadden, Patrick and Ray, Rupa and Hardeman, Klaas and Coley, Andrew M. and Foley, Michael and Haystead, Timothy A. }, citeulike-article-id = {2191724}, doi = {http://dx.doi.org/10.1124/mol.62.6.1364}, journal = {Mol Pharmacol}, keywords = {disease, drugdiscovery, hcs, proteomics, purine}, month = {December}, number = {6}, pages = {1364--1372}, posted-at = {2008-01-03 16:04:44}, priority = {0}, title = {Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome}, url = {http://dx.doi.org/10.1124/mol.62.6.1364}, volume = {62}, year = {2002} }

TY - JOUR ID - citeulike:2191724 L3 - citeulike-article-id:2191724 TI - Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome JF - Mol Pharmacol VL - 62 IS - 6 SP - 1364 EP - 1372 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 [gamma]-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 the Plasmodium 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. 10.1124/mol.62.6.1364 KW - disease KW - drugdiscovery KW - hcs KW - proteomics KW - purine AU - Graves, Paul AU - Kwiek, Jesse AU - Fadden, Patrick AU - Ray, Rupa AU - Hardeman, Klaas AU - Coley, Andrew AU - Foley, Michael AU - Haystead, Timothy PY - 2002/12/01/ UR - http://dx.doi.org/10.1124/mol.62.6.1364 ER -