TEMPLATE-MEDIATED BIOMINERALIZATION OF HEMOZOIN

Duquesne University, Pittsburgh PA

Investigators

Abstract

DESCRIPTION: (verbatim from applicant's abstract) Malaria, resulting from the parasites of the genus Plasmodium, places an untold burden on the global population. As recently as 40 years ago, only 10 percent of the world's population was at risk from malaria. Today, over 40 percent of the world's population is at risk. The disease, endemic in 91 countries, infects 300-500 million people and results in the deaths of over 2 million children annually. The economic burden placed on developing countries reached 2.0 billion dollars (US) annually in 1995 and is predicted to climb. Due to increased parasite resistance to traditional antimalarials and vector resistance to insecticides, malaria is once again resurgent. New strategies to combat malaria must focus on parasite-specific biochemical processes such as the detoxification of excess heme produced in the catabolism of hemoglobin. The detoxification pathway involves the formation of a unique coordination polymer of hemes known as hemozoin. Although recent studies have implicated a class of histidine-rich proteins as playing a critical role in the formation of this critical detoxification polymer, little is known about the function of these proteins in the nucleation and crystallization of hemozoin. This proposal will investigate the role of the histidine-rich proteins (HRP) of P. falciparum in the biomineralization of hemozoin using a novel dendrimeric peptide bionucleating template that incorporates a minimal set of recognition motifs from HRP II that promote the nucleation and crystallization of hemozoin. Specifically, it is proposed to: 1) Determine those components of the heme moiety critical for the interactions between heme substrate and nucleating domain by using topologically defined metalloporphyrins and related complexes as probes. 2) Elucidate the role of nucleating domain active site amino acids in the formation of hemozoin using a synthetic mutagenesis approach. The successful completion of this proposal will lead to a molecular level model detailing the interactions critical for the nucleation and crystallization of hemozoin. With such understanding, it will be possible to examine the disruption of these interactions, ultimately leading to viable therapeutic agents.