Inhibition of efflux of quinolines as new therapeutic strategy in malaria.

Abstract

Plasmodium falciparum is one of the most lethal parasite responsible for human malaria. Until now, the only one solution to counter malaria is the use of antimalarial drugs. Unfortunately, the extensively use of drugs, such as quinolines (i.e. chloroquine, quinine or mefloquine), have led to the emergence of drug resistance. Chloroquine and probably other quinolines act in interfering in the detoxification of hematin in the digestive vacuole. Quinolines are accumulated in P. falciparum digestive vacuole and the accumulation varies from a susceptible strain to a resistant one. Nevertheless, the mechanisms of quinoline resistance are still investigating. Genetic polymorphisms in some strains have been linked to drug resistance. The modifications observed are mutations on genes that encode transport proteins localized in the membrane of digestive vacuole. Three transporters were involved in quinoline resistance: PfCRT (Plasmodium falciparum chloroquine resistance transporter), Pgh1 (P-glycoprotein homologue 1) and PfMRP (Plasmodium falciparum multidrug resistance protein). They could be involved in accumulation or efflux mechanisms of drugs. In order to understand their role in resistance, localization, encoding gene structure, protein structure and endogenous function of these three transporters are reported. Some molecules that have no intrinsic antimalarial effect have been shown to reverse drug resistance when they are combined to chloroquine, quinine or mefloquine. These molecules are a solution to counter resistance but also they are precious tools to elucidate the resistance mechanisms. The molecules that have already shown a capacity to reverse chloroquine, quinine or mefloquine resistances were reported. Some of them could act on one of the three transporters involved in drug resistance, by confirming their role in quinoline resistance. Here we summarize the main elements of quinoline resistance and reversion of quinoline resistance related to malaria.

• Authors: Maud Henry, Sandrine Alibert, Christophe Rogier, Jacques Barbe, Bruno Pradines
• Journal: Current topics in medicinal chemistry (Curr Top Med Chem) Vol. 8 Issue 7 Pg. 563-78 ( 2008) ISSN: 1873-4294 [Electronic] United Arab Emirates
• PMID: 18473883 (Publication Type: Journal Article, Review)

Chemical References

• ATP-Binding Cassette Transporters
• Antimalarials
• Carrier Proteins
• Membrane Transport Proteins
• PfCRT protein, Plasmodium falciparum
• Protozoan Proteins
• Quinolines
• mdr gene protein, Plasmodium

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Antimalarials (chemistry, pharmacology)
• Carrier Proteins (metabolism)
• Drug Resistance (drug effects)
• Humans
• Malaria, Falciparum (drug therapy)
• Membrane Transport Proteins (metabolism)
• Plasmodium falciparum (drug effects, metabolism)
• Protozoan Proteins (metabolism)
• Quinolines (metabolism, pharmacology)