Date of Award

Fall 2007

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological Sciences

Program/Concentration

Biology

Committee Director

Roland A. Cooper

Committee Member

Wayne Hynes

Committee Member

Christopher Osgood

Call Number for Print

Special Collections LD4331.B46 L358 2007

Abstract

Chloroquine (CQ) resistant Plasmodium falciparum is a serious problem affecting 3.2 billion people in over 100 countries today. Most endemic malarious countries are among the poorest in the world and lack the resources to replace the inexpensive and highly effective CQ. CQ resistance (CQR) reversal agents are a potentially inexpensive solution to restoring CQ efficacy. CQR reversal agents are drugs that have little to no antimalarial activity alone, but in combination with CQ, they increase dmg accumulation in the parasite and enhance the sensitivity to CQ in CQR parasites. PfCRT is a putative transporter located on the parasite digestive vacuole membrane and is causally associated with CQ resistance. Evidence also suggests that the resistance reversal phenomenon is mediated through PfCRT. To investigate the molecular mechanism of CQR reversal and PfCRT interaction, in vitro drug assays were performed and structure activity relationships in CQR reversal agents were identified to test the hypothesis that PfCRT mediates CQR reversal. Fourteen antimalarials and reversal agents were tested for intrinsic activity against a panel of PfCRT mutant parasites generated in the 106/1 genetic background. Four of the reversal agents were then selected for resistance reversal assays against CQ and quinine (QN). Drug responses varied with PfCRT polymorphisms indicating direct interaction between PfCRT and reversal agents of diverse structural classes. The combined inherent activity and reversal results are consistent with the hypothesis that PfCRT does modulate CQR reversal agent activity in the panel of PfCRT mutants tested.

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DOI

10.25777/3jkw-fp14

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