Hemozoin: Crystal Engineering Survivability

AbstractDuring the intraerythrocytic stages of malaria infection, the parasite consumes host hemoglobin as a nutrient source, resulting in the liberation of free heme. In order to survive, the malaria parasite utilizes a unique detoxification pathway in which this toxic free heme is converted to the nontoxic biomineral hemozoin. Structurally, hemozoin consists of reciprocal head‐to‐tail dimeric units of heme bound through propionate O‐Fe(III). The propionic acid groups of the heme dimer then hydrogen‐bond with other dimers to form the extended crystal. Disruption of this crystallization process results in parasite death, and therefore serves as an important strategy for drug design. Hemozoin formation does not occur spontaneously at a physiologically relevant rate, and identification of the biological mediator of this crystal remained elusive for many years. Although hemozoin has been studied since the 18th century, scientists have only begun to obtain a detailed understanding of the structure and formation of this biomineral in the last 25 years. Current studies strongly support the hypothesis that neutral lipid bodies present within the parasite are the biological template for hemozoin crystallization. When synthetic neutral lipid bodies (SNLDs) were replicatedin vitro, it was found that Fe(III)PPIX rapidly accumulates within these SNLDs. Furthermore, the SNLDs have been shown to serve as a kinetically competent site for β‐hematin formation (synthetic hemozoin). This new paradigm for hemozoin formation was rapidly translated into an improved high‐throughput screening assay that effectively recapitulated the physiological environment and will allow for improved hit to lead development of new antimalarial drugs.