Intimate Molecular Interactions of P. falciparum Merozoite Proteins Involved in Invasion of Red Blood Cells and Their Implications for Vaccine Design Luis Eduardo Rodriguez, †,‡,| Hernando Curtidor, †,‡,| Mauricio Urquiza, † Gladys Cifuentes, † Claudia Reyes, † and Manuel Elkin Patarroyo* ,†,§ Fundacio ´n Instituto de Inmunologı ´a de Colombia, Carrera 50 No. 26-00, Bogota ´, Colombia Received December 13, 2006 Contents 1. Introduction 3656 1.1. Merozoite’s Structure 3658 1.1.1. Rhoptries 3658 1.1.2. Micronemes 3660 1.1.3. Dense Granules 3660 1.2. P. falciparum Infection-Induced RBC Structures (Maurer’s Clefts) 3660 1.3. Merozoite Proteins Involved in RBC Invasion 3660 2. Defining Target Molecules for Triggering a Protection-Inducing Immune Response 3660 2.1. Synthetic Peptides Used for Acquiring Knowledge about Merozoite Protein RBC Binding Regions 3661 2.2. Rationale for High-Activity Binding Peptide Recognition 3661 3. Merozoite Surface Protein (MSP) Family 3662 3.1. Merozoite Surface Protein-1 (MSP-1) 3664 3.2. Merozoite Surface Protein-2 (MSP-2) 3675 3.3. Merozoite Surface Protein-3 (MSP-3) 3677 3.4. Merozoite Surface Protein-4 (MSP-4) 3677 3.5. Merozoite Surface Protein-5 (MSP-5) 3678 3.6. Merozoite Surface Protein-6 (MSP-6) 3678 3.7. Merozoite Surface Protein-7 (MSP-7) 3678 3.8. Merozoite Surface Protein-8 (MSP-8) 3679 3.9. Merozoite Surface Protein-9 (MSP-9) or Acid Basic Repeat Antigen (ABRA) 3679 3.10. Merozoite Surface Protein-10 (MSP-10) 3680 3.11. Glycophorin Binding Protein-130 (GBP-130) 3681 3.12. Serine Repeat Antigen-5 (SERA-5) 3681 3.13. Lipid Raft-Associated Plasmodium falciparum Cys6 Peptide Family 3682 4. Microneme Proteins 3683 4.1. Erythrocyte Binding-like (EBL) Family 3683 4.1.1. Erythrocyte Binding Antigen-175 (EBA-175) 3683 4.1.2. Erythrocyte Binding Antigen-181 (EBA-181) or JESEBL 3684 4.1.3. Erythrocyte Binding Antigen-140 (EBA-140) or BAEBL 3685 4.1.4. Erythrocyte Binding-like-1 (EBL-1) 3685 4.2. Apical Membrane Antigen-1 (AMA-1) 3686 4.3. MAEBL 3687 4.4. Plasmodium Thrombospondin-Related Apical Merozoite Protein (PTRAMP) 3687 5. Rhoptry Proteins 3688 5.1. Reticulocyte Binding-like Protein Family (RBL) 3688 5.1.1. Plasmodium falciparum Normocyte Binding Protein-1 (PfNBP-1) or Plasmodium falciparum Reticulocyte Binding Protein-Homologue-1 (PfRBP-H1) 3688 5.1.2. Reticulocyte Binding Protein-2 Homologues a and b (PfRBP-2Ha and -2Hb) 3689 5.2. Rhoptry-Associated Protein-1 (RAP-1) 3689 5.3. Rhoptry-Associated Protein-2 (RAP-2) 3690 5.4. Rhoptry-Associated Protein-3 (RAP-3) 3690 5.5. Rhoptry-Associated Membrane Antigen (RAMA) 3690 5.6. RhopH3 3691 5.7. Cytoadherence-Linked Asexual Gene (RhopH-1/CLAG 3.2) 3692 6. Infected RBC (iRBC) Membrane-Associated P. falciparum Proteins and Transportome-Associated Proteins 3692 6.1. Ring-Infected Erythrocyte Surface Antigen (RESA)-155 3692 6.2. RESA-like Protein 3693 6.3. Histidine-Rich Proteins 3693 6.4. P. falciparum Erythrocyte Membrane Protein-1 (PfEMP-1) 3694 7. Supporting Background for the Subunit-based Synthetic Vaccine Concept 3695 7.1. Conserved HABP Structural Characteristics 3695 7.1.1. Functional and Structural Compartmentalization of Merozoite Proteins Involved in RBC Invasion 3695 7.1.2. Minimal Subunit-based Synthetic Peptide Vaccine Concept is Correct 3697 8. Implications for Vaccine Design and Perspectives 3698 9. Acknowledgments 3699 10. References 3699 1. Introduction Malaria continues to be one of the main public health problems for mankind; it is the transmissible disease with the greatest morbidity and mortality around the world. It kills * To whom correspondence should be addressed. Tel.: +57-1-3244672, +57-1-4815219. Fax: +57-1-4815269. E-mail: mepatarr@gmail.com, mepatarr@fidic.org.co. † Fundacion Instituto de Inmunologı ´a de Colombia (FIDIC). ‡ Universidad del Rosario. | These authors contributed equally to this work. § Universidad Nacional de Colombia. Chem. Rev. 2008, 108, 3656–3705 3656 10.1021/cr068407v CCC: $71.00  2008 American Chemical Society Published on Web 08/19/2008