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Vol. 62, Issue 6, 1364-1372, December 2002
Department of Pharmacology and Cancer Biology, Center for Chemical
Biology, Duke University, Durham, North Carolina (P.R.G., J.J.K., R.R.,
T.A.J.H.); Serenex Inc., Durham, North Carolina (P.F., K.H.);
Department of Pharmacology and Program in Molecular Medicine,
University of Virginia, Charlottesville, Virginia (J.J.K.); and
Department of Biochemistry and the Cooperative Research Centre for
Diagnostics, La Trobe University, Melbourne, Australia (A.M.C., M.F.)
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 
-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.
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