Photoaffinity labeling of mefloquine-binding proteins in human serum, uninfected erythrocytes and Plasmodium falciparum-infected erythrocytes.
A photoreactive quinolinemethanol analog, N-[4-[1-hydroxy-2-(dibutylamino)ethyl]quinolin-8yl]-4- azido-2-salicylamide (ASA-MQ) has been synthesized which closely mimics the action of mefloquine. ASA-MQ possesses potent antimalarial activity against a mefloquine-sensitive strain of Plasmodium falciparum and shows decreased activity against a mefloquine-resistant parasite strain. Radioiodinated ASA-MQ has been used in photoaffinity labeling studies to identify mefloquine-interacting proteins in serum, uninfected erythrocytes and Plasmodium falciparum-infected erythrocytes. We have shown that mefloquine interacts specifically with apo-A1, the major protein of serum high density lipoproteins. In addition, mefloquine was shown to interact specifically with the erythrocyte membrane protein, band 7.2b (stomatin). A further two high affinity mefloquine-binding proteins with apparent molecular masses of 22 and 36 kDa were identified in three different strains of Plasmodium falciparum. We suggest that these two mefloquine-binding parasite proteins may be involved in the uptake of mefloquine or may represent macromolecular targets of mefloquine action in malaria parasites.
Desneves
J
J
School of Chemistry, La Trobe University, Victoria, Australia.
Thorn
G
G
Berman
A
A
Galatis
D
D
La Greca
N
N
Sinding
J
J
Foley
M
M
Deady
L W
LW
Cowman
A F
AF
Tilley
L
L
D000345:Affinity Labels; D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism*; D004351:Drug Resistance; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D015767:Mefloquine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins; D010963:Plasmodium falciparum / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism*
D000345:Affinity Labels; D000962:Antimalarials; D016632:Apolipoprotein A-I; D001798:Blood Proteins; D008565:Membrane Proteins; D015800:Protozoan Proteins; C036860:STOM protein, human; D015767:Mefloquine