Dominican University of California
 

Poster Presentations - Guzman Lecture Hall

Presentation or Panel Title

Investigation of Structure-Activity Relationships of Antimalarial Drugs Through Novel Plasmodium falciparum Chloroquine Resistance Resistance Transporter (PfCRT)

Location

Guzman Lecture Hall Poster #3

Start Date

4-24-2015 10:30 AM

End Date

4-24-2015 11:30 AM

Department

Natural Sciences and Mathematics

Student Type

Undergraduate

Faculty Mentor

Roland A. Cooper

Presentation Format

Poster Presentation

Abstract/Description

Mutation in the P. falciparum resistance chloroquine transporter (PfCRT) protein causes chloroquine resistance and alters susceptibility to various antimalarial drugs. Mutant PfCRT transports chloroquine out of the parasite digestive vacuole; however, the molecular details of drug-receptor interaction are poorly understood. The antiviral drug amantadine has moderate potency against P. falciparum and acts to reduce the level of chloroquine resistance determined by the pfcrt haplotype. In accordance, chloroquine-resistant parasites show enhanced sensitivity to amantadine. We used continuous, step-wise amantadine selection on three chloroquine-resistant lines of the P. falciparum 106/1 strain. Each of these lines contains a unique pfcrt allele differing only by a non-synonymous SNP in codon 76, resulting in PfCRT K76I, K76N or K76T, but otherwise contains an identical genetic background. Stepwise selection with amantadine resulted in parasite lines with six novel pfcrt alleles. Parasites showed resistance to amantadine, increased chloroquine sensitivity, and changes in susceptibility to other digestive vacuole-targeting drugs. The results shed light on new topographical regions of the PfCRT protein and amino acid residues involved in drug interactions and digestive vacuole morphology. Two additional amantadine-selected parasite clones, derived from 106/1 K76N and K76I, showed amantadine resistance and altered quinoline susceptibility without accompanying mutations in pfcrt. These parasite lines are currently under investigation. Our results increase the understanding of how digestive vacuole-targeting drugs interact with the PfCRT protein and explain patters of cross-resistance in the malaria parasite.

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Apr 24th, 10:30 AM Apr 24th, 11:30 AM

Investigation of Structure-Activity Relationships of Antimalarial Drugs Through Novel Plasmodium falciparum Chloroquine Resistance Resistance Transporter (PfCRT)

Guzman Lecture Hall Poster #3

Mutation in the P. falciparum resistance chloroquine transporter (PfCRT) protein causes chloroquine resistance and alters susceptibility to various antimalarial drugs. Mutant PfCRT transports chloroquine out of the parasite digestive vacuole; however, the molecular details of drug-receptor interaction are poorly understood. The antiviral drug amantadine has moderate potency against P. falciparum and acts to reduce the level of chloroquine resistance determined by the pfcrt haplotype. In accordance, chloroquine-resistant parasites show enhanced sensitivity to amantadine. We used continuous, step-wise amantadine selection on three chloroquine-resistant lines of the P. falciparum 106/1 strain. Each of these lines contains a unique pfcrt allele differing only by a non-synonymous SNP in codon 76, resulting in PfCRT K76I, K76N or K76T, but otherwise contains an identical genetic background. Stepwise selection with amantadine resulted in parasite lines with six novel pfcrt alleles. Parasites showed resistance to amantadine, increased chloroquine sensitivity, and changes in susceptibility to other digestive vacuole-targeting drugs. The results shed light on new topographical regions of the PfCRT protein and amino acid residues involved in drug interactions and digestive vacuole morphology. Two additional amantadine-selected parasite clones, derived from 106/1 K76N and K76I, showed amantadine resistance and altered quinoline susceptibility without accompanying mutations in pfcrt. These parasite lines are currently under investigation. Our results increase the understanding of how digestive vacuole-targeting drugs interact with the PfCRT protein and explain patters of cross-resistance in the malaria parasite.