STRUCTURAL AND FUNCTIONAL-PROPERTIES OF REGION II-PLUS OF THE MALARIACIRCUMSPOROZOITE PROTEIN

During feeding, infected mosquitos inject malaria sporozoites into the host circulation. Within minutes, the parasites are found in the live r where they initiate the first stage of malaria infection. All specie s of malaria sporozoites are uniformly covered by the circumsporozoite protein (CS), which contains a conserved COOH-terminal sequence calle d region II-plus. We have previously shown that region II-plus is the parasite's hepatocyte-binding ligand and that this ligand binds to hep aran sulfate proteoglycans (HSPGs) on the hepatocyte membrane. Using a series of substituted region II-plus peptides, we show here that the downstream basic amino acids as well as the interdispersed hydrophobic residues are required for binding of CS to hepatocyte HSPGs. We also show that this positively charged stretch of amino acids must be aggre gated in order to bind to the receptor. On the basis of this informati on, we have synthesized a multiple antigen peptide that mimics the hep atocyte-binding ligand. This construct inhibits both CS binding to Hep G2 cells in vitro as well as CS clearance in mice.