Targeting Chloroquine Resistance with Fe(III) Complexes

Sharma, Vijay

Abstract

Emergence of chloroquine-resistant Plasmodium falciparum species is a major obstacle to chemotherapy of malaria. In addition to the need for discovery of novel antimalarials, exploration of mechanism(s) of chloroquine resistance has become of paramount importance. Recently, patterns of chloroquine resistance in P. falciparum have been mapped to a 36 kb segment of chromosome 7 harboring a small cluster of genes, including cg2, a gene encoding a unique 330 kDa protein with complex polymorphisms. Recently, we have discovered a novel agent, a 3-methoxy-substituted amine phenolate metal(III) complex (MR045), that selectively targets chloroquine-resistant clones associated with specific polymorphisms in this 36 kb segment. This lead compound inhibits the parasite heme polymerization reaction, the same putative target as chloroquine, but traverses the chloroquine resistance mechanism in all strains tested to date. Therefore, this agent can be a tool to explore mechanism(s) of chloroquine resistance and provides a promising lead for generation of novel drug candidates for use in the chemotherapy of chloroquine resistant disease. We have observed that slight variations in the position of functionalities in the peripheral regions of the organic scaffold, not the central metal core, impart the unique targeting properties to MR045. Therefore, we propose to further explore structure-activity relationships by synthesis of additional analogues based on this lead compound, identify candidate chloroquine resistance proteins by synthesis of photoaffinity analogues to probe cell extracts, and localize the drug in cells in situ by incorporation of fluorophores in the motif for correlation with the location of candidate chloroquine resistance proteins. These versatile metal(III) complexes will also be radiolabeled and used in binding, transport and competitive biochemical assays with membranes, digestive vacuoles, and purified CG2 in relation to the chloroquine resistance phenotype. While providing novel reagents as biochemical probes of the mechanism(s) of chloroquine resistance, this project also will provide candidate drugs that target chloroquine resistant organisms.