Exploration of Drug Science

Table 3. Peptides of MSP-9, their sequence and in vitro invasion inhibition with 200 μM

Peptide	AA	Sequence*	Invasion inhibition (% ± SD)
2148	20	¹²¹LQSHKKLIKALKKNIESYQN¹⁴⁰	95 ± 14
2149	20	¹⁴¹KKHLIYKNKSYNPLLLSCVK¹⁶⁰	97 ± 12
2150	20	¹⁶¹KMNMLKENVDYIQKNQNLFK¹⁸⁰	25 ± 17
2152	20	²⁰¹YKSQGHKKETSQNQNENNDN²²⁰	16 ± 3
2153	20	²²¹QKYQEVNDEDDVNDEEDTND²⁴⁰	0 ± 0

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* The bolded residues are variable residues across different strains; purple is for changes in 3D7 and 7G8 strains. MSP-9: merozoite surface protein 9; AA: aminoacids

Declarations

Acknowledgments

This review is dedicated to the memory of our esteemed mentor, Prof. Manuel E. Patarroyo, whose visionary leadership, unwavering dedication to scientific inquiry, and invaluable mentorship were instrumental in shaping the research that we have summarized and reviewed here. His profound contributions to immunology and malaria research have left an enduring legacy that continues to inspire future generations of scientists. Sadly, Prof. Patarroyo passed away during the preparation of this manuscript, but his impact on the field and his relentless pursuit of knowledge will always be remembered. This dedication also extends to the many scientists from FIDIC and the former Instituto de Inmunología, who, despite numerous challenges, persevered with unwavering commitment to advancing this research. Their dedication, resilience, and collective efforts have significantly contributed to our understanding of Plasmodium falciparum merozoite invasion, paving the way for future advancements in malaria control and vaccine development.

Author contributions

MUM: Conceptualization, Investigation, Project administration, Validation, Writing—original draft. DBR: Investigation, Validation, Visualization, Writing—review & editing. FGQ: Conceptualization, Validation, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

Fanny Guzmán-Quimbayo who is the Guest Editor of Exploration of Drug Science had no involvement in the decision-making or the review process of this manuscript. The other authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The dataset analyzed for this study can be found on the PDB Homepage (https://www.rcsb.org/) and AlphaFold Protein Database (https://alphafold.com/). Additionally, the sequences of the proteins that were constructed by AlphaFold Server were taken from UniProt (https://www.uniprot.org/). The database used to search for articles was PubMed (https://pubmed.ncbi.nlm.nih.gov/) where the keywords used were “Plasmodium falciparum + peptides + (Name of the protein)”, for the articles done in Instituto de Inmunología “Patarroyo ME” was added to the search. The software Protein BLAST by NCBI was used to determine the conserved regions of the peptides in different strains, while the sequences of the strains were obtained from UniProt.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

World Malaria Report 2023 [Internet]. WHO; c2025 [cited 2025 Feb 20]. Available from: https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2023

Liu Q, Jing W, Kang L, Liu J, Liu M. Trends of the global, regional and national incidence of malaria in 204 countries from 1990 to 2019 and implications for malaria prevention. J Travel Med. 2021;28:taab046. [DOI] [PubMed] [PMC]

Manzoni G, Try R, Guintran JO, Christiansen-Jucht C, Jacoby E, Sovannaroth S, et al. Progress towards malaria elimination in the Greater Mekong Subregion: perspectives from the World Health Organization. Malar J. 2024;23:64. [DOI] [PubMed] [PMC]

Villena OC, Arab A, Lippi CA, Ryan SJ, Johnson LR. Influence of environmental, geographic, socio-demographic, and epidemiological factors on presence of malaria at the community level in two continents. Sci Rep. 2024;14:16734. [DOI] [PubMed] [PMC]

Cowman AF, Healer J, Marapana D, Marsh K. Malaria: Biology and Disease. Cell. 2016;167:610–24. [DOI] [PubMed]

Cowman AF, Tonkin CJ, Tham WH, Duraisingh MT. The Molecular Basis of Erythrocyte Invasion by Malaria Parasites. Cell Host Microbe. 2017;22:232–45. [DOI] [PubMed]

Cowman AF, Crabb BS. Invasion of red blood cells by malaria parasites. Cell. 2006;124:755–66. [DOI] [PubMed]

Ord RL, Rodriguez M, Yamasaki T, Takeo S, Tsuboi T, Lobo CA. Targeting sialic acid dependent and independent pathways of invasion in Plasmodium falciparum. PLoS One. 2012;7:e30251. [DOI] [PubMed] [PMC]

Molina-Franky J, Patarroyo ME, Kalkum M, Patarroyo MA. The Cellular and Molecular Interaction Between Erythrocytes and Plasmodium falciparum Merozoites. Front Cell Infect Microbiol. 2022;12:816574. [DOI] [PubMed] [PMC]

10.

Gaur D, Mayer DC, Miller LH. Parasite ligand-host receptor interactions during invasion of erythrocytes by Plasmodium merozoites. Int J Parasitol. 2004;34:1413–29. [DOI] [PubMed]

11.

Pasvol G. How many pathways for invasion of the red blood cell by the malaria parasite? Trends Parasitol. 2003;19:430–2. [DOI] [PubMed]

12.

Rodriguez LE, Curtidor H, Urquiza M, Cifuentes G, Reyes C, Patarroyo ME. Intimate molecular interactions of P. falciparum merozoite proteins involved in invasion of red blood cells and their implications for vaccine design. Chem Rev. 2008;108:3656–705. [DOI] [PubMed]

13.

Kumar H, Tolia NH. Getting in: The structural biology of malaria invasion. PLoS Pathog. 2019;15:e1007943. [DOI] [PubMed] [PMC]

14.

Burzyńska P, Jodłowska M, Zerka A, Czujkowski J, Jaśkiewicz E. Red Blood Cells Oligosaccharides as Targets for Plasmodium Invasion. Biomolecules. 2022;12:1669. [DOI] [PubMed] [PMC]

15.

Jaskiewicz E, Jodłowska M, Kaczmarek R, Zerka A. Erythrocyte glycophorins as receptors for Plasmodium merozoites. Parasit Vectors. 2019;12:317. [DOI] [PubMed] [PMC]

16.

Suarez JE, Urquiza M, Curtidor H, Rodriguez LE, Ocampo M, Torres E, et al. A GBP 130 derived peptide from Plasmodium falciparum binds to human erythrocytes and inhibits merozoite invasion in vitro. Mem Inst Oswaldo Cruz. 2000;95:495–501. [DOI] [PubMed]

17.

Reed MB, Caruana SR, Batchelor AH, Thompson JK, Crabb BS, Cowman AF. Targeted disruption of an erythrocyte binding antigen in Plasmodium falciparum is associated with a switch toward a sialic acid-independent pathway of invasion. Proc Natl Acad Sci U S A. 2000;97:7509–14. [DOI] [PubMed] [PMC]

18.

Awandare GA, Nyarko PB, Aniweh Y, Ayivor-Djanie R, Stoute JA. Plasmodium falciparum strains spontaneously switch invasion phenotype in suspension culture. Sci Rep. 2018;8:5782. [DOI] [PubMed] [PMC]

19.

Beeson JG, Drew DR, Boyle MJ, Feng G, Fowkes FJ, Richards JS. Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria. FEMS Microbiol Rev. 2016;40:343–72. [DOI] [PubMed] [PMC]

20.

Das S, Hertrich N, Perrin AJ, Withers-Martinez C, Collins CR, Jones ML, et al. Processing of Plasmodium falciparum Merozoite Surface Protein MSP1 Activates a Spectrin-Binding Function Enabling Parasite Egress from RBCs. Cell Host Microbe. 2015;18:433–44. [DOI] [PubMed] [PMC]

21.

Miller LH, Roberts T, Shahabuddin M, McCutchan TF. Analysis of sequence diversity in the Plasmodium falciparum merozoite surface protein-1 (MSP-1). Mol Biochem Parasitol. 1993;59:1–14. [DOI] [PubMed]

22.

Laurens MB. RTS,S/AS01 vaccine (Mosquirix™): an overview. Hum Vaccin Immunother. 2020;16:480–9. [DOI] [PubMed] [PMC]

23.

Seidlein LV. Roll out and prospects of the malaria vaccine R21/Matrix-M. PLoS Med. 2025;22:e1004515. [DOI] [PubMed] [PMC]

24.

Palacpac NMQ, Horii T. RH5.1/Matrix-M: highlighting blood-stage malaria vaccines. Lancet Infect Dis. 2025;25:472–3. [DOI] [PubMed]

25.

Regules JA, Cummings JF, Ockenhouse CF. The RTS,S vaccine candidate for malaria. Expert Rev Vaccines. 2011;10:589–99. [DOI] [PubMed]

26.

Cummings JF, Polhemus ME, Kester KE, Ockenhouse CF, Gasser RA Jr, Coyne P, et al.; RTS,S Vaccine Evaluation Group. A phase IIa, randomized, double-blind, safety, immunogenicity and efficacy trial of Plasmodium falciparum vaccine antigens merozoite surface protein 1 and RTS,S formulated with AS02 adjuvant in healthy, malaria-naïve adults. Vaccine. 2024;42:3066–74. [DOI] [PubMed]

27.

Baldwin MR, Li X, Hanada T, Liu SC, Chishti AH. Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells. Blood. 2015;125:2704–11. [DOI] [PubMed] [PMC]

28.

Lin CS, Uboldi AD, Epp C, Bujard H, Tsuboi T, Czabotar PE, et al. Multiple Plasmodium falciparum Merozoite Surface Protein 1 Complexes Mediate Merozoite Binding to Human Erythrocytes. J Biol Chem. 2016;291:7703–15. [DOI] [PubMed] [PMC]

29.

Howell SA, Hackett F, Jongco AM, Withers-Martinez C, Kim K, Carruthers VB, et al. Distinct mechanisms govern proteolytic shedding of a key invasion protein in apicomplexan pathogens. Mol Microbiol. 2005;57:1342–56. [DOI] [PubMed]

30.

Boyle MJ, Richards JS, Gilson PR, Chai W, Beeson JG. Interactions with heparin-like molecules during erythrocyte invasion by Plasmodium falciparum merozoites. Blood. 2010;115:4559–68. [DOI] [PubMed]

31.

Nikodem D, Davidson E. Identification of a novel antigenic domain of Plasmodium falciparum merozoite surface protein-1 that specifically binds to human erythrocytes and inhibits parasite invasion, in vitro. Mol Biochem Parasitol. 2000;108:79–91. [DOI] [PubMed]

32.

Jäschke A, Coulibaly B, Remarque EJ, Bujard H, Epp C. Merozoite Surface Protein 1 from Plasmodium falciparum Is a Major Target of Opsonizing Antibodies in Individuals with Acquired Immunity against Malaria. Clin Vaccine Immunol. 2017;24:e00155–17. [DOI] [PubMed] [PMC]

33.

Woehlbier U, Epp C, Kauth CW, Lutz R, Long CA, Coulibaly B, et al. Analysis of antibodies directed against merozoite surface protein 1 of the human malaria parasite Plasmodium falciparum. Infect Immun. 2006;74:1313–22. [DOI] [PubMed] [PMC]

34.

John CC, O’Donnell RA, Sumba PO, Moormann AM, de Koning-Ward TF, King CL, et al. Evidence that invasion-inhibitory antibodies specific for the 19-kDa fragment of merozoite surface protein-1 (MSP-1 19) can play a protective role against blood-stage Plasmodium falciparum infection in individuals in a malaria endemic area of Africa. J Immunol. 2004;173:666–72. [DOI] [PubMed]

35.

Dijkman PM, Marzluf T, Zhang Y, Chang SS, Helm D, Lanzer M, et al. Structure of the merozoite surface protein 1 from Plasmodium falciparum. Sci Adv. 2021;7:eabg0465. [DOI] [PubMed] [PMC]

36.

Urquiza M, Rodriguez LE, Suarez JE, Guzmán F, Ocampo M, Curtidor H, et al. Identification of Plasmodium falciparum MSP-1 peptides able to bind to human red blood cells. Parasite Immunol. 1996;18:515–26. [DOI] [PubMed]

37.

Thouvenel CD, Fontana MF, Netland J, Krishnamurty AT, Takehara KK, Chen Y, et al. Multimeric antibodies from antigen-specific human IgM+ memory B cells restrict Plasmodium parasites. J Exp Med. 2021;218:e20200942. [DOI] [PubMed] [PMC]

38.

Pizarro JC, Chitarra V, Verger D, Holm I, Pêtres S, Dartevelle S, et al. Crystal structure of a Fab complex formed with PfMSP1-19, the C-terminal fragment of merozoite surface protein 1 from Plasmodium falciparum: a malaria vaccine candidate. J Mol Biol. 2003;328:1091–103. [DOI] [PubMed]

39.

Parra M, Hui G, Johnson AH, Berzofsky JA, Roberts T, Quakyi IA, et al. Characterization of conserved T- and B-cell epitopes in Plasmodium falciparum major merozoite surface protein 1. Infect Immun. 2000;68:2685–91. [DOI] [PubMed] [PMC]

40.

Lozano JM, Espejo F, Ocampo M, Salazar LM, Tovar D, Barrera N, et al. Mapping the anatomy of a Plasmodium falciparum MSP-1 epitope using pseudopeptide-induced mono- and polyclonal antibodies and CD and NMR conformation analysis. J Struct Biol. 2004;148:110–22. [DOI] [PubMed]

41.

Egan A, Waterfall M, Pinder M, Holder A, Riley E. Characterization of human T- and B-cell epitopes in the C terminus of Plasmodium falciparum merozoite surface protein 1: evidence for poor T-cell recognition of polypeptides with numerous disulfide bonds. Infect Immun. 1997;65:3024–31. [DOI] [PubMed] [PMC]

42.

Ayieko C, Maue AC, Jura WG, Noland GS, Ayodo G, Rochford R, et al. Changes in B Cell Populations and Merozoite Surface Protein-1-Specific Memory B Cell Responses after Prolonged Absence of Detectable P. falciparum Infection. PLoS One. 2013;8:e67230. [DOI] [PubMed] [PMC]

43.

Valero MV, Amador LR, Galindo C, Figueroa J, Bello MS, Murillo LA, et al. Vaccination with SPf66, a chemically synthesised vaccine, against Plasmodium falciparum malaria in Colombia. Lancet. 1993;341:705–10. [DOI] [PubMed]

44.

6ZBH | pdb_00006zbh [Internet]. [Cited 2025 Apr 21]. Available from: https://www.rcsb.org/structure/6ZBH

45.

6XQW Crystal Structure of MaliM03 Fab in complex with Pfmsp1-19 [Internet]. [Cited 2025 Apr 21]. Available from: https://pdbj.org/mine/summary/6xqw?lang=zh-CN

46.

1OB1 Crystal structure of a Fab complex whith Plasmodium falciparum MSP1-19 [Internet]. [Cited 2025 Apr 21]. Available from: https://pdbj.org/mine/summary/1ob1?lang=zh-CN

47.

8DFG Crystal structure of potently neutralizing human monoclonal antibody 42D6 Fab in complex with MSP1-19 [Internet]. [Cited 2025 Apr 21]. Available from: https://pdbj.org/mine/summary/8dfg?lang=zh-CN

48.

Uthaipibull C, Aufiero B, Syed SE, Hansen B, Guevara Patiño JA, Angov E, et al. Inhibitory and blocking monoclonal antibody epitopes on merozoite surface protein 1 of the malaria parasite Plasmodium falciparum. J Mol Biol. 2001;307:1381–94. [DOI] [PubMed]

49.

Jennings RM. Murine and human antibody responses to Plasmodium falciparum merozoite surface protein-1 [dissertation]. University of London; 2004.

50.

Lazarou M, Guevara Patiño JA, Jennings RM, McIntosh RS, Shi J, Howell S, et al. Inhibition of erythrocyte invasion and Plasmodium falciparum merozoite surface protein 1 processing by human immunoglobulin G1 (IgG1) and IgG3 antibodies. Infect Immun. 2009;77:5659–67. [DOI] [PubMed] [PMC]

51.

Gerold P, Schofield L, Blackman MJ, Holder AA, Schwarz RT. Structural analysis of the glycosyl-phosphatidylinositol membrane anchor of the merozoite surface proteins-1 and -2 of Plasmodium falciparum. Mol Biochem Parasitol. 1996;75:131–43. [DOI] [PubMed]

52.

Genton B, Betuela I, Felger I, Al-Yaman F, Anders RF, Saul A, et al. A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. J Infect Dis. 2002;185:820–7. [DOI] [PubMed]

53.

Yman V, White MT, Asghar M, Sundling C, Sondén K, Draper SJ, et al. Antibody responses to merozoite antigens after natural Plasmodium falciparum infection: kinetics and longevity in absence of re-exposure. BMC Med. 2019;17:22. [DOI] [PubMed] [PMC]

54.

Holder AA. Proteins on the surface of the malaria parasite and cell invasion. Parasitology. 1994;108:S5–18. [DOI] [PubMed]

55.

Adda CG, Murphy VJ, Sunde M, Waddington LJ, Schloegel J, Talbo GH, et al. Plasmodium falciparum merozoite surface protein 2 is unstructured and forms amyloid-like fibrils. Mol Biochem Parasitol. 2009;166:159–71. [DOI] [PubMed] [PMC]

56.

Boyle MJ, Langer C, Chan JA, Hodder AN, Coppel RL, Anders RF, et al. Sequential processing of merozoite surface proteins during and after erythrocyte invasion by Plasmodium falciparum. Infect Immun. 2014;82:924–36. [DOI] [PubMed] [PMC]

57.

Chauhan VS, Yazdani SS, Gaur D. Malaria vaccine development based on merozoite surface proteins of Plasmodium falciparum. Hum Vaccin. 2010;6. [PubMed]

58.

Mosqueda J, McElwain TF, Stiller D, Palmer GH. Babesia bovis merozoite surface antigen 1 and rhoptry-associated protein 1 are expressed in sporozoites, and specific antibodies inhibit sporozoite attachment to erythrocytes. Infect Immun. 2002;70:1599–603. [DOI] [PubMed] [PMC]

59.

Ocampo M, Urquiza M, Guzmán F, Rodriguez LE, Suarez J, Curtidor H, et al. Two MSA 2 peptides that bind to human red blood cells are relevant to Plasmodium falciparum merozoite invasion. J Pept Res. 2000;55:216–23. [DOI] [PubMed]

60.

Chandley P, Ranjan R, Kumar S, Rohatgi S. Host-parasite interactions during Plasmodium infection: Implications for immunotherapies. Front Immunol. 2023;13:1091961. [DOI] [PubMed] [PMC]

61.

Smythe JA, Coppel RL, Day KP, Martin RK, Oduola AM, Kemp DJ, et al. Structural diversity in the Plasmodium falciparum merozoite surface antigen 2. Proc Natl Acad Sci U S A. 1991;88:1751–5. [DOI] [PubMed] [PMC]

62.

Eacret JS, Gonzales DM, Franks RG, Burns JM Jr. Immunization with merozoite surface protein 2 fused to a Plasmodium-specific carrier protein elicits strain-specific and strain-transcending, opsonizing antibody. Sci Rep. 2019;9:9022. [DOI] [PubMed] [PMC]

63.

Reddy SB, Anders RF, Beeson JG, Färnert A, Kironde F, Berenzon SK, et al. High affinity antibodies to Plasmodium falciparum merozoite antigens are associated with protection from malaria. PLoS One. 2012;7:e32242. [DOI] [PubMed] [PMC]

64.

Krishnarjuna B, Andrew D, MacRaild CA, Morales RA, Beeson JG, Anders RF, et al. Strain-transcending immune response generated by chimeras of the malaria vaccine candidate merozoite surface protein 2. Sci Rep. 2016;6:20613. [DOI] [PubMed] [PMC]

65.

Hill DL, Wilson DW, Sampaio NG, Eriksson EM, Ryg-Cornejo V, Harrison GLA, et al. Merozoite Antigens of Plasmodium falciparum Elicit Strain-Transcending Opsonizing Immunity. Infect Immun. 2016;84:2175–84. [DOI] [PubMed] [PMC]

66.

Adda CG, MacRaild CA, Reiling L, Wycherley K, Boyle MJ, Kienzle V, et al. Antigenic characterization of an intrinsically unstructured protein, Plasmodium falciparum merozoite surface protein 2. Infect Immun. 2012;80:4177–85. [DOI] [PubMed] [PMC]

67.

Morales RAV, MacRaild CA, Seow J, Krishnarjuna B, Drinkwater N, Rouet R, et al. Structural basis for epitope masking and strain specificity of a conserved epitope in an intrinsically disordered malaria vaccine candidate. Sci Rep. 2015;5:10103. [DOI] [PubMed] [PMC]

68.

MacRaild CA, Pedersen MØ, Anders RF, Norton RS. Lipid interactions of the malaria antigen merozoite surface protein 2. Biochim Biophys Acta. 2012;1818:2572–8. [DOI] [PubMed]

69.

Crystal Structure of anti-MSP2 Fv fragment (mAb6D8)in complex with MSP2 11-23 [Internet]. [Cited 2025 Apr 21]. Available from: https://www.ebi.ac.uk/pdbe/entry/pdb/4r3s/index

70.

Hasting CH. Novel malaria parasite proteins involved in erythrocyte invasion [dissertation]. University College London; 2012.

71.

Gaur D, Chitnis CE, Chauhan VS. Molecular basis of erythrocyte invasion by Plasmodium merozoites. In: Gaur D, Chitnis CE, Chauhan VS, editors. Advances in Malaria Research. John Wiley & Sons, Ltd; 2016. pp. 33–86.

72.

Li X, Chen H, Oo TH, Daly TM, Bergman LW, Liu SC, et al. A Co-ligand Complex Anchors Plasmodium falciparum Merozoites to the Erythrocyte Invasion Receptor Band 3. J Biol Chem. 2004;279:5765–71. [DOI]

73.

Lee SH, Kang HJ, Chu KB, Basak S, Lee DH, Moon EK, et al. Protective Immunity Induced by Virus-Like Particle Containing Merozoite Surface Protein 9 of Plasmodium berghei. Vaccines (Basel). 2020;8:428. [DOI] [PubMed] [PMC]

74.

Curtidor H, Urquiza M, Suarez JE, Rodriguez LE, Ocampo M, Puentes A, et al. Plasmodium falciparum acid basic repeat antigen (ABRA) peptides: erythrocyte binding and biological activity. Vaccine. 2001;19:4496–504. [DOI] [PubMed]

75.

Sharma P, Kumar A, Singh B, Bharadwaj A, Sailaja VN, Adak T, et al. Characterization of protective epitopes in a highly conserved Plasmodium falciparum antigenic protein containing repeats of acidic and basic residues. Infect Immun. 1998;66:2895–904. [DOI] [PubMed] [PMC]

76.

Hodder AN, Crewther PE, Matthew ML, Reid GE, Moritz RL, Simpson RJ, et al. The disulfide bond structure of Plasmodium apical membrane antigen-1. J Biol Chem. 1996;271:29446–52. [DOI] [PubMed]

77.

Narum DL, Thomas AW. Differential localization of full-length and processed forms of PF83/AMA-1 an apical membrane antigen of Plasmodium falciparum merozoites. Mol Biochem Parasitol. 1994;67:59–68. [DOI] [PubMed]

78.

Bargieri DY, Andenmatten N, Lagal V, Thiberge S, Whitelaw JA, Tardieux I, et al. Apical membrane antigen 1 mediates apicomplexan parasite attachment but is dispensable for host cell invasion. Nat Commun. 2013;4:2552. [DOI] [PubMed] [PMC]

79.

Patarroyo ME, Arevalo-Pinzon G, Reyes C, Moreno-Vranich A, Patarroyo MA. Malaria Parasite Survival Depends on Conserved Binding Peptides’ Critical Biological Functions. Curr Issues Mol Biol. 2016;18:57–78. [PubMed]

80.

Woehlbier U, Epp C, Hackett F, Blackman MJ, Bujard H. Antibodies against multiple merozoite surface antigens of the human malaria parasite Plasmodium falciparum inhibit parasite maturation and red blood cell invasion. Malar J. 2010;9:77. [DOI] [PubMed] [PMC]

81.

Dutta S, Haynes JD, Barbosa A, Ware LA, Snavely JD, Moch JK, et al. Mode of action of invasion-inhibitory antibodies directed against apical membrane antigen 1 of Plasmodium falciparum. Infect Immun. 2005;73:2116–22. [DOI] [PubMed] [PMC]

82.

Pizarro JC, Vulliez-Le Normand B, Chesne-Seck ML, Collins CR, Withers-Martinez C, Hackett F, et al. Crystal structure of the malaria vaccine candidate apical membrane antigen 1. Science. 2005;308:408–11. [DOI] [PubMed]

83.

Ssewanyana I, Rek J, Rodriguez I, Wu L, Arinaitwe E, Nankabirwa JI, et al. Impact of a Rapid Decline in Malaria Transmission on Antimalarial IgG Subclasses and Avidity. Front Immunol. 2021;11:576663. [DOI] [PubMed] [PMC]

84.

Urquiza M, Suarez JE, Cardenas C, Lopez R, Puentes A, Chavez F, et al. Plasmodium falciparum AMA-1 erythrocyte binding peptides implicate AMA-1 as erythrocyte binding protein. Vaccine. 2000;19:508–13. [DOI] [PubMed]

85.

Shi YP, Hasnain SE, Sacci JB, Holloway BP, Fujioka H, Kumar N, et al. Immunogenicity and in vitro protective efficacy of a recombinant multistage Plasmodium falciparum candidate vaccine. Proc Natl Acad Sci U S A. 1999;96:1615–20. [DOI] [PubMed] [PMC]

86.

4R19 | pdb_00004r19 [Internet]. [Cited 2025 Apr 21]. Available from: https://www.rcsb.org/structure/4R19

87.

Apical membrane antigen 1 (AF-P50492-F1) [Internet]. [Cited 2025 Apr 21]. Available from: https://alphafold.ebi.ac.uk/entry/P50492

88.

3ZWZ | pdb_00003zwz [Internet]. [Cited 2025 Apr 21]. Available from: https://www.rcsb.org/structure/3ZWZ

89.

Coley AM, Gupta A, Murphy VJ, Bai T, Kim H, Foley M, et al. Structure of the malaria antigen AMA1 in complex with a growth-inhibitory antibody. PLoS Pathog. 2007;3:1308–19. [DOI] [PubMed] [PMC]

90.

Structure of the malaria antigen AMA1 in complex with a growth-inhibitory antibody [Internet]. [Cited 2025 Apr 21]. Available from: https://www.ebi.ac.uk/pdbe/entry/pdb/2q8a/index

91.

Vulliez-Le Normand B, Tonkin ML, Lamarque MH, Langer S, Hoos S, Roques M, et al. Structural and functional insights into the malaria parasite moving junction complex. PLoS Pathog. 2012;8:e1002755. [DOI] [PubMed] [PMC]

92.

Sterkers Y, Scheidig C, da Rocha M, Lepolard C, Gysin J, Scherf A. Members of the low-molecular-mass rhoptry protein complex of Plasmodium falciparum bind to the surface of normal erythrocytes. J Infect Dis. 2007;196:617–21. [DOI]

93.

Saul A, Miller LH. A robust neutralization test for Plasmodium falciparum malaria. J Exp Med. 2001;193:F51–4. [DOI] [PubMed] [PMC]

94.

Stowers A, Taylor D, Prescott N, Cheng Q, Cooper J, Saul A. Assessment of the humoral immune response against Plasmodium falciparum rhoptry-associated proteins 1 and 2. Infect Immun. 1997;65:2329–38. [DOI] [PubMed] [PMC]

95.

Ridley RG, Takacs B, Etlinger H, Scaife JG. A rhoptry antigen of Plasmodium falciparum is protective in Saimiri monkeys. Parasitology. 1990;101:187–92. [DOI] [PubMed]

96.

Favuzza P, Blaser S, Dreyer AM, Riccio G, Tamborrini M, Thoma R, et al. Generation of Plasmodium falciparum parasite-inhibitory antibodies by immunization with recombinantly-expressed CyRPA. Malar J. 2016;15:161. [DOI] [PubMed] [PMC]

97.

Harnyuttanakorn P, McBride JS, Donachie S, Heidrich HG, Ridley RG. Inhibitory monoclonal antibodies recognise epitopes adjacent to a proteolytic cleavage site on the RAP-1 protein of Plasmodium falciparum. Mol Biochem Parasitol. 1992;55:177–86. [DOI] [PubMed]

98.

Curtidor H, Ocampo M, Tovar D, López R, García J, Valbuena J, et al. Specific erythrocyte binding capacity and biological activity of Plasmodium falciparum-derived rhoptry-associated protein 1 peptides. Vaccine. 2004;22:1054–62. [DOI] [PubMed]

99.

Rhoptry associated protein-1 (AF-Q9U414-F1) [Internet]. EMBL; c2022 [cited 2025 Mar 8]. Available from: https://alphafold.ebi.ac.uk/entry/Q9U414

100.

Howard RF, Jacobson KC, Rickel E, Thurman J. Analysis of inhibitory epitopes in the Plasmodium falciparum rhoptry protein RAP-1 including identification of a second inhibitory epitope. Infect Immun. 1998;66:380–6. [DOI] [PubMed] [PMC]

101.

Moreno R, Pöltl-Frank F, Stüber D, Matile H, Mutz M, Weiss NA, et al. Rhoptry-associated protein 1-binding monoclonal antibody raised against a heterologous peptide sequence inhibits Plasmodium falciparum growth in vitro. Infect Immun. 2001;69:2558–68. [DOI] [PubMed] [PMC]

102.

The role of cis-regulatory elements in Plasmodium falciparum transcriptional regulation [Internet]. Nanyang Technological University; c2019 [cited 2025 Mar 8]. Available from: https://dr.ntu.edu.sg/entities/publication/c218bc06-5208-4dff-b724-bf4a7359ad05

103.

Aronson NE, Silverman C, Wasserman GF, Kochan J, Hall BT, Esser K, et al. Immunization of owl monkeys with a recombinant protein containing repeated epitopes of a Plasmodium falciparum glycophorin-binding protein. Am J Trop Med Hyg. 1991;45:548–59. [DOI] [PubMed]

104.

Lyon JA, Thomas AW, Hall T, Chulay JD. Specificities of antibodies that inhibit merozoite dispersal from malaria-infected erythrocytes. Mol Biochem Parasitol. 1989;36:77–85. [DOI]

105.

Johnson Y, Shakri AR, Pond-Tor S, Jnawali A, Najrana T, Wu H, et al. Immunization with PfGBP130 generates antibodies that inhibit RBC invasion by P. falciparum parasites. Front Immunol. 2024;15:1350560. [DOI] [PubMed] [PMC]

106.

Kochan J, Perkins M, Ravetch JV. A tandemly repeated sequence determines the binding domain for an erythrocyte receptor binding protein of P. falciparum. Cell. 1986;44:689–96. [DOI] [PubMed]

107.

Glycophorin-binding protein [Internet]. EMBL; c 2022 [cited 2025 Mar 8]. Available from: https://alphafold.ebi.ac.uk/entry/P02895

108.

Debrabant A, Maes P, Delplace P, Dubremetz JF, Tartar A, Camus D. Intramolecular mapping of Plasmodium falciparum P126 proteolytic fragments by N-terminal amino acid sequencing. Mol Biochem Parasitol. 1992;53:89–95. [DOI] [PubMed]

109.

Yeoh S, O’Donnell RA, Koussis K, Dluzewski AR, Ansell KH, Osborne SA, et al. Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes. Cell. 2007;131:1072–83. [DOI] [PubMed]

110.

Li J, Matsuoka H, Mitamura T, Horii T. Characterization of proteases involved in the processing of Plasmodium falciparum serine repeat antigen (SERA). Mol Biochem Parasitol. 2002;120:177–86. [DOI] [PubMed]

111.

Stallmach R, Kavishwar M, Withers-Martinez C, Hackett F, Collins CR, Howell SA, et al. Plasmodium falciparum SERA5 plays a non-enzymatic role in the malarial asexual blood-stage lifecycle. Mol Microbiol. 2015;96:368–87. [DOI] [PubMed] [PMC]

112.

Iyer GR, Singh S, Kaur I, Agarwal S, Siddiqui MA, Bansal A, et al. Calcium-dependent phosphorylation of Plasmodium falciparum serine repeat antigen 5 triggers merozoite egress. J Biol Chem. 2018;293:9736–46. [DOI] [PubMed] [PMC]

113.

Arisue N, Palacpac NMQ, Tougan T, Horii T. Characteristic features of the SERA multigene family in the malaria parasite. Parasit Vectors. 2020;13:170. [DOI] [PubMed] [PMC]

114.

Pang XL, Horii T. Complement-mediated killing of Plasmodium falciparum erythrocytic schizont with antibodies to the recombinant serine repeat antigen (SERA). Vaccine. 1998;16:1299–305. [DOI] [PubMed]

115.

Pang XL, Mitamura T, Horii T. Antibodies reactive with the N-terminal domain of Plasmodium falciparum serine repeat antigen inhibit cell proliferation by agglutinating merozoites and schizonts. Infect Immun. 1999;67:1821–7. [DOI] [PubMed] [PMC]

116.

Banyal HS, Inselburg J. Isolation and characterization of parasite-inhibitory Plasmodium falciparum monoclonal antibodies. Am J Trop Med Hyg. 1985;34:1055–64. [DOI] [PubMed]

117.

Inselburg J, Bzik DJ, Li WB, Green KM, Kansopon J, Hahm BK, et al. Protective immunity induced in Aotus monkeys by recombinant SERA proteins of Plasmodium falciparum. Infect Immun. 1991;59:1247–50. [DOI] [PubMed] [PMC]

118.

Puentes A, Garcia J, Vera R, Lopez QR, Urquiza M, Vanegas M, et al. Serine repeat antigen peptides which bind specifically to red blood cells. Parasitol Int. 2000;49:105–17. [DOI] [PubMed]

119.

Yagi M, Bang G, Tougan T, Palacpac NMQ, Arisue N, Aoshi T, et al. Protective epitopes of the Plasmodium falciparum SERA5 malaria vaccine reside in intrinsically unstructured N-terminal repetitive sequences. PLoS One. 2014;9:e98460. [DOI]

120.

Crystal Structure Analysis of SERA5E from plasmodium falciparum with loop 690-700 ordered [Internet]. EMBL-EBI; c2012 [cited 2025 Mar 5]. Available from: https://www.ebi.ac.uk/pdbe/entry/pdb/2wbf/index

121.

Rydzak J, Kaczmarek R, Czerwinski M, Lukasiewicz J, Tyborowska J, Szewczyk B, et al. The baculovirus-expressed binding region of Plasmodium falciparum EBA-140 ligand and its glycophorin C binding specificity. PLoS One. 2015;10:e0115437. [DOI]

122.

Maier AG, Baum J, Smith B, Conway DJ, Cowman AF. Polymorphisms in erythrocyte binding antigens 140 and 181 affect function and binding but not receptor specificity in Plasmodium falciparum. Infect Immun. 2009;77:1689–99. [DOI] [PubMed] [PMC]

123.

Zerka A, Kaczmarek R, Czerwinski M, Jaskiewicz E. Plasmodium reichenowi EBA-140 merozoite ligand binds to glycophorin D on chimpanzee red blood cells, shedding new light on origins of Plasmodium falciparum. Parasit Vectors. 2017;10:554. [DOI] [PubMed] [PMC]

124.

Lopaticki S, Maier AG, Thompson J, Wilson DW, Tham WH, Triglia T, et al. Reticulocyte and erythrocyte binding-like proteins function cooperatively in invasion of human erythrocytes by malaria parasites. Infect Immun. 2011;79:1107–17. [DOI] [PubMed] [PMC]

125.

Salinas ND, Tang WK, Tolia NH. Blood-Stage Malaria Parasite Antigens: Structure, Function, and Vaccine Potential. J Mol Biol. 2019;431:4259–80. [DOI] [PubMed]

126.

Baro B, Kim CY, Lin C, Kongsomboonvech AK, Tetard M, Peterson NA, et al. Plasmodium falciparum exploits CD44 as a coreceptor for erythrocyte invasion. Blood. 2023;142:2016–28. [DOI] [PubMed] [PMC]

127.

Gilberger TW, Thompson JK, Reed MB, Good RT, Cowman AF. The cytoplasmic domain of the Plasmodium falciparum ligand EBA-175 is essential for invasion but not protein trafficking. J Cell Biol. 2003;162:317–27. [DOI] [PubMed] [PMC]

128.

Kobayashi K, Takano R, Takemae H, Sugi T, Ishiwa A, Gong H, et al. Analyses of interactions between heparin and the apical surface proteins of Plasmodium falciparum. Sci Rep. 2013;3:3178. [DOI] [PubMed] [PMC]

129.

Healer J, Thompson JK, Riglar DT, Wilson DW, Chiu YH, Miura K, et al. Vaccination with conserved regions of erythrocyte-binding antigens induces neutralizing antibodies against multiple strains of Plasmodium falciparum. PLoS One. 2013;8:e72504. [DOI] [PubMed] [PMC]

130.

Tijani MK, Babalola OA, Odaibo AB, Anumudu CI, Asinobi AO, Morenikeji OA, et al. Acquisition, maintenance and adaptation of invasion inhibitory antibodies against Plasmodium falciparum invasion ligands involved in immune evasion. PLoS One. 2017;12:e0182187. [DOI] [PubMed] [PMC]

131.

Rodriguez LE, Ocampo M, Vera R, Puentes A, Lopez R, Garcia J, et al. Plasmodium falciparum EBA-140 kDa protein peptides that bind to human red blood cells. J Pept Res. 2003;62:175–84. [DOI] [PubMed]

132.

4JNO | pdb_00004jno [Internet]. [Cited 2025 Mar 5]. Available from: https://www.rcsb.org/structure/4JNO

133.

Chiu CY, White MT, Healer J, Thompson JK, Siba PM, Mueller I, et al. Different Regions of Plasmodium falciparum Erythrocyte-Binding Antigen 175 Induce Antibody Responses to Infection of Varied Efficacy. J Infect Dis. 2016;214:96–104. [DOI] [PubMed]

134.

Jones TR, Narum DL, Gozalo AS, Aguiar J, Fuhrmann SR, Liang H, et al. Protection of Aotus monkeys by Plasmodium falciparum EBA-175 region II DNA prime-protein boost immunization regimen. J Infect Dis. 2001;183:303–12. [DOI] [PubMed]

135.

Narum DL, Haynes JD, Fuhrmann S, Moch K, Liang H, Hoffman SL, et al. Antibodies against the Plasmodium falciparum receptor binding domain of EBA-175 block invasion pathways that do not involve sialic acids. Infect Immun. 2000;68:1964–6. [DOI] [PubMed] [PMC]

136.

Sim BK, Narum DL, Liang H, Fuhrmann SR, Obaldia N 3rd, Gramzinski R, et al. Induction of biologically active antibodies in mice, rabbits, and monkeys by Plasmodium falciparum EBA-175 region II DNA vaccine. Mol Med. 2001;7:247–54. [PubMed] [PMC]

137.

Irani V, Ramsland PA, Guy AJ, Siba PM, Mueller I, Richards JS, et al. Acquisition of Functional Antibodies That Block the Binding of Erythrocyte-Binding Antigen 175 and Protection Against Plasmodium falciparum Malaria in Children. Clin Infect Dis. 2015;61:1244–52. [DOI] [PubMed] [PMC]

138.

Rodriguez LE, Urquiza M, Ocampo M, Suarez J, Curtidor H, Guzman F, et al. Plasmodium falciparum EBA-175 kDa protein peptides which bind to human red blood cells. Parasitology. 2000;120:225–35. [DOI] [PubMed]

139.

Sim BK. Delineation of functional regions on Plasmodium falciparum EBA-175 by antibodies eluted from immune complexes. Mol Biochem Parasitol. 1998;95:183–92. [DOI] [PubMed]

140.

1ZRL | pdb_00001zrl [Internet]. [Cited 2025 Mar 5]. Available from: https://www.rcsb.org/structure/1ZRL

141.

Erythrocyte-binding antigen 175 [Internet]. EMBL; c2022 [cited 2025 Mar 5]. Available: https://alphafold.ebi.ac.uk/entry/P19214

142.

Chen E, Paing MM, Salinas N, Sim BK, Tolia NH. Structural and functional basis for inhibition of erythrocyte invasion by antibodies that target Plasmodium falciparum EBA-175. PLoS Pathog. 2013;9:e1003390. [DOI] [PubMed] [PMC]

144.

Tolia NH, Enemark EJ, Sim BK, Joshua-Tor L. Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum. Cell. 2005;122:183–93. [DOI] [PubMed]

145.

Sim BK, Narum DL, Chattopadhyay R, Ahumada A, Haynes JD, Fuhrmann SR, et al. Delineation of stage specific expression of Plasmodium falciparum EBA-175 by biologically functional region II monoclonal antibodies. PLoS One. 2011;6:e18393. [DOI] [PubMed] [PMC]

146.

4QEX | pdb_00004qex [Internet]. [Cited 2025 Mar 5]. Available from: https://www.rcsb.org/structure/4QEX

147.

Kals E, Kals M, Lees RA, Introini V, Kemp A, Silvester E, et al. Application of optical tweezer technology reveals that PfEBA and PfRH ligands, not PfMSP1, play a central role in Plasmodium falciparum merozoite-erythrocyte attachment. PLoS Pathog. 2024;20:e1012041. [DOI] [PubMed] [PMC]

148.

Paul G, Deshmukh A, Kumar Chourasia B, Kalamuddin M, Panda A, Kumar Singh S, et al. Protein-protein interaction studies reveal the Plasmodium falciparum merozoite surface protein-1 region involved in a complex formation that binds to human erythrocytes. Biochem J. 2018;475:1197–209. [DOI] [PubMed]

149.

Wilson DW, Crabb BS, Beeson JG. Development of fluorescent Plasmodium falciparum for in vitro growth inhibition assays. Malar J. 2010;9:152. [DOI] [PubMed] [PMC]

150.

Hendry JA, Kwiatkowski D, McVean G. Elucidating relationships between P.falciparum prevalence and measures of genetic diversity with a combined genetic-epidemiological model of malaria. PLoS Comput Biol. 2021;17:e1009287. [DOI] [PubMed] [PMC]

151.

Goodman AL, Draper SJ. Blood-stage malaria vaccines - recent progress and future challenges. Ann Trop Med Parasitol. 2010;104:189–211. [DOI] [PubMed]

152.

Richards JS, Beeson JG. The future for blood-stage vaccines against malaria. Immunol Cell Biol. 2009;87:377–90. [DOI] [PubMed]

153.

Jun H, Mazigo E, Lee WJ, Louis JM, Syahada JH, Fitriana F, et al. Estimation of PfRh5-based vaccine efficacy in asymptomatic Plasmodium falciparum patients from high-endemic areas of Tanzania using genetic and antigenicity variation screening. Front Immunol. 2024;15:1495513. [DOI] [PubMed] [PMC]

154.

Thomson-Luque R, Stabler TC, Fürle K, Silva JC, Daubenberger C. Plasmodium falciparum merozoite surface protein 1 as asexual blood stage malaria vaccine candidate. Expert Rev Vaccines. 2024;23:160–73. [DOI] [PubMed]

155.

Rodríguez-Obediente K, Yepes-Pérez Y, Benavides-Ortiz D, Díaz-Arévalo D, Reyes C, Arévalo-Pinzón G, et al. Invasion-inhibitory peptides chosen by natural selection analysis as an antimalarial strategy. Mol Immunol. 2023;163:86–103. [DOI] [PubMed]

156.

Li W, Joshi MD, Singhania S, Ramsey KH, Murthy AK. Peptide Vaccine: Progress and Challenges. Vaccines (Basel). 2014;2:515–36. [DOI] [PubMed] [PMC]

157.

Lauterbach SB, Lanzillotti R, Coetzer TL. Construction and use of Plasmodium falciparum phage display libraries to identify host parasite interactions. Malar J. 2003;2:47. [DOI] [PubMed] [PMC]

158.

Keizer DW, Miles LA, Li F, Nair M, Anders RF, Coley AM, et al. Structures of phage-display peptides that bind to the malarial surface protein, apical membrane antigen 1, and block erythrocyte invasion. Biochemistry. 2003;42:9915–23. [DOI] [PubMed]

159.

Ranjan R, Chugh M, Kumar S, Singh S, Kanodia S, Hossain MJ, et al. Proteome analysis reveals a large merozoite surface protein-1 associated complex on the Plasmodium falciparum merozoite surface. J Proteome Res. 2011;10:680–91. [DOI] [PubMed]

160.

Zerka A, Rydzak J, Lass A, Szostakowska B, Nahorski W, Wroczyńska A, et al. Studies on Immunogenicity and Antigenicity of Baculovirus-Expressed Binding Region of Plasmodium falciparum EBA-140 Merozoite Ligand. Arch Immunol Ther Exp (Warsz). 2016;64:149–56. [DOI] [PubMed] [PMC]

161.

Espejo F, Bermúdez A, Torres E, Urquiza M, Rodríguez R, López Y, et al. Shortening and modifying the 1513 MSP-1 peptide's alpha-helical region induces protection against malaria. Biochem Biophys Res Commun. 2004;315:418–27. [DOI] [PubMed]

162.

Aza-Conde J, Reyes C, Suárez CF, Patarroyo MA, Patarroyo ME. The molecular basis for peptide-based antimalarial vaccine development targeting erythrocyte invasion by P. falciparum. Biochem Biophys Res Commun. 2021;534:86–93. [DOI] [PubMed]