Modifying Gene Expression to Expose Plasmodium falciparum to Immune System Attack

Downregulation of malarial rif gene expression, a process implicated in malarial evasion of the human immune system, has been linked with repressor protein binding to the DNA element ATGCAA in Plasmodium falciparum. A Pyrrole- and Imidazole-containing polyamide was designed with the purpose of recognizing that DNA sequence based on previously reported pairing rules. The polyamide was also designed to target P. falciparum over mammalian cells by exploitation of the protozoal P2 aminopurine transporter. It is hypothesized that the target molecule, by blocking repressor protein binding, will effectively enhance rif gene expression in P. falciparum, allowing immune destruction of the protozoan. The following will be described: the synthesis of the target compound, a thorough analysis of the compound’s binding affinity and selectivity for the DNA sequence ATGCAA (using thermal melts, CD, ITC, and DNA footprinting), the in vitro cytotoxicity against mammalian cells and P. falciparum, and an investigation into the ability of the compound to alter rif gene expression in the parasite (using real-time PCR)