title: Saquinavir inhibits the malaria parasite's chloroquine resistance transporter.
abstract: The antiretroviral protease inhibitors (APIs) ritonavir, saquinavir, and lopinavir, used to treat HIV infection, inhibit the growth of Plasmodium falciparum at clinically relevant concentrations. Moreover, it has been reported that these APIs potentiate the activity of chloroquine (CQ) against this parasite in vitro. The mechanism underlying this effect is not understood, but the degree of chemosensitization varies between the different APIs and, with the exception of ritonavir, appears to be dependent on the parasite exhibiting a CQ-resistant phenotype. Here we report a study of the role of the P. falciparum chloroquine resistance transporter (PfCRT) in the interaction between CQ and APIs, using transgenic parasites expressing different PfCRT alleles and using the Xenopus laevis oocyte system for the heterologous expression of PfCRT. Our data demonstrate that saquinavir behaves as a CQ resistance reverser and that this explains, at least in part, its ability to enhance the effects of CQ in CQ-resistant P. falciparum parasites.
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT, Australia. Rowena.Martin@anu.edu.au
authors.forename: Rowena E
authors.initials: RE
authors.lastname: Martin
authors.forename: Alice S
authors.initials: AS
authors.lastname: Butterworth
authors.forename: Donald L
authors.initials: DL
authors.lastname: Gardiner
authors.forename: Kiaran
authors.initials: K
authors.lastname: Kirk
authors.forename: James S
authors.initials: JS
authors.lastname: McCarthy
authors.forename: Tina S
authors.initials: TS
authors.lastname: Skinner-Adams
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000494:pharmacology; D014316:Tritium; D014982:Xenopus laevis
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D014316:Tritium; D061466:Lopinavir; D002738:Chloroquine; D019258:Saquinavir; D019438:Ritonavir