The long term objectives of this application are to define the mechanisms involved in invasion of hepatocytes by sporozoites and to develop specific inhibitors.
Our specific aims are: (1) to analyze the structural requirements for the recognition of region II-plus of the CS by heparan sulfate proteoglycan (HSPG) receptors on hepatocytes; (2) to study in mice the role of region II-plus in the clearance and fate of intravenously injected CS, and determine whether injected synthetic peptides representing region II-plus are targeted to hepatocytes; (3) to inhibit malarial infection in vitro and in vivo by preventing the recognition of sporozoite CS by the HSPG hepatocyte receptors. This will be attempted by competitive inhibition with region II-plus synthetic peptides. Because the region II-plus motif is found in other parasite proteins, in thrombospondin, properdin, the terminal complement components C6 through C9, F-spondin and UNC-5 (molecules involved in the development of the nervous system), the characterization of the region II-plus motif should have applications outside the malaria field. The results of these studies will be of relevance to the development of immunoprophylactic agents and drugs to treat malaria infection. Small molecule mimetic drug engineering is an emerging strategy in pharmaceutical research. In particular, the peptidomimetic approaches (including the design of conformationally restricted peptides), based on molecular modeling, have already been used to probe receptor biology and to create beta-turn mimics. Our studies may also have practical applications in gene therapy: it is conceivable that the specificity of region II-plus of CS for hepatocytes can be utilized to deliver genetic information to these cells in vivo.
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