Erythrocyte binding peptides: a story in the search for a malaria vaccine

Abstract

Merozoite invasion of erythrocytes relies on molecular interactions between parasite and host proteins, making these proteins potential therapeutic targets. This review summarizes research on Plasmodium falciparum merozoite invasion conducted at the Instituto de Inmunología, San Juan de Dios Hospital, between 1990 and 2000. Erythrocyte-binding analyses of P. falciparum proteins merozoite surface protein 1 (MSP-1), MSP-2, acid basic repeat antigen (ABRA) (MSP-9), apical membrane antigen-1 (AMA-1), rhoptry-associated protein 1 (RAP-1), glycophorin-binding protein 130 (GBP-130), serine repeat antigen 5 (SERA-5), erythrocyte-binding antigen 140 (EBA-140), and EBA-175 identified 50 high-activity binding peptides (HABPs) with nanomolar-range dissociation constants. Most of these peptides inhibit merozoite invasion and belong to erythrocyte-binding regions of their respective proteins. Several HABPs overlap with epitopes recognized by inhibitory monoclonal antibodies (mAbs). MSP-1 HABP-5501 contains epitopes for mAbs 12.8, 12.10, MaliM03 fragment antigen binding (Fab), and 42D6 Fab, all of which block invasion. MSP-2 HABPs include epitopes targeted by opsonizing antibodies, while MSP-9 HABPs (2148–2153) interact with Band 3 during invasion. AMA-1 HABPs (4315, 4316, and 4325) contribute to the 1F9 epitope, a key target of immune recognition. RAP-1 HABP-26188 elicits inhibitory antibodies, including cross-reactive mAbs SP5.2 and SP8.18, the latter displaying parasite growth inhibition. GBP-130 HABP-2220 binds glycophorin and induces invasion-blocking antibodies. SERA-5 HABP-6725 contains sequences targeted by native SERA-5 antibodies, while HABPs 6727 and 6733 are recognized by antibodies from natural infection and vaccination. EBA-140 HABPs (26135, 26144, and 26147) are located in Region II (RII) and are recognized by mAbs with moderate to strong neutralizing activity. EBA-175 HABPs (1779, 1783, 1814, 1815, and 1818) are in recombinant fragments recognized by antibodies eluted from immune complexes. HABPs 1779 and 1783, located in RII, bind erythrocytes independently of sialic acid, inhibit rRII-EBA binding, and interact with α(2,3)-sialyllactose. HABP-1783 also contains the target site of mAb R217, which potently blocks EBA-175 binding to glycophorin A and inhibits invasion.

Keywords

HABPs / merozoite invasion / P. falciparum / peptides / malaria

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