Discovery of novel targets of quinoline drugs in the human purine binding proteome.
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.
Graves
Paul R
PR
Department of Pharmacology and Cancer Biology, Center for Chemical Biology, Duke University, Durham, North Carolina 27710, USA.
Kwiek
Jesse J
JJ
Fadden
Patrick
P
Ray
Rupa
R
Hardeman
Klaas
K
Coley
Andrew M
AM
Foley
Michael
M
Haystead
Timothy A J
TA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism*; D002738:Chloroquine / Q000737:chemistry / Q000378:metabolism; D002847:Chromatography, Agarose; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000737:chemistry; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D015767:Mefloquine / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D010963:Plasmodium falciparum / Q000737:chemistry / Q000187:drug effects / Q000254:growth & development; D011319:Primaquine / Q000737:chemistry / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D050697:Retinal Dehydrogenase; D012685:Sepharose / Q000737:chemistry
D000962:Antimalarials; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020543:Proteome; D002738:Chloroquine; D000255:Adenosine Triphosphate; D012685:Sepharose; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D011319:Primaquine; D015767:Mefloquine