CYTOADHERENCE-BLOCKING PEPTIDES AS A THERAPY FOR MALARIA

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Plasmodium falciparum, the most malignant of the four human malarias, contributes to 1-2 million deaths annually. The hallmark of P. falciparum infections is sequestration - the attachment of erythrocytes infected with mature stage parasites (trophozoites/schizonts) to endothelial cells lining the post-capillary venules. Sequestration in the brain microvessels - cerebral malaria--may totally occlude blood flown and result in deep coma and death. Through the use of murine monoclonal antibodies (Mabs) it has been possible to show that parasite-induced modifications in the erythrocyte membrane protein band 3 are directly involved in in vitro adhesion (cytoadherence); it is conceivable these proteins also play a role in vivo (sequestration/cerebral malaria). Based on molecular mapping of the modified forms of band 3 with these anti- adhesion Mabs, peptides were synthesized. Several of these peptides inhibited cytoadherence. To precisely define the sequences critical to adhesion, overlapping peptides corresponding to the amino acids surrounding and included within the binding region of these peptides will be prepared by solid phase synthesis. Peptides will be tested singly and in combination for their capacity to inhibit cytoadherence, and those with the greatest inhibitory activity will be administered to P. falciparum-infected monkeys to determine their capacity for reversal of sequestration. Antisera to the peptides will be prepared in mice, and peptides will be used to vaccinate monkeys. The antisera will be used for epitope mapping and for assessment of strain specificity; anti- sequestering activity of the antisera will be determined, both in vitro and by passive transfer experiments in monkeys. The ligand to which the adhesin binds will be identified using anti-idiotype antibodies and affinity chromatography with immobilized peptide. The administration of adhesion-inhibiting peptides to comatose cerebral malaria patients should unplug microvessels containing packed parasitized red cells and bring the patient out of coma Anti-adhesion therapy and/or vaccination would be ideal in areas where malaria is hyperendemic, since it would reduce both mortality and morbidity in those individuals who were most susceptible-- young children without any natal immunity.