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Definition
Malaria is spread by Anopheles mosquitoes, the protozoan parasite grows and multiplies within erythrocytes in its asexual cycle. Different malaria peptides were isolated by human antibodies in plasma samples of individuals exposed to chronic malaria.

Discovery
The first approach of a malaria peptide vaccine was a polymeric chimeric molecule named SPf66, which conferred limited protective efficacy in monkey and human trial 1. Apical membrane antigen-1 is a protein found in the merozoite stage of the malaria parasite Plasmodium falciparum and has been shown to be critical in the invasion of host erythrocytes. Using a random peptide library displayed on the surface of phage, several peptides were identified which specifically recognized and bound to P. falciparum antigen 2. Different malaria peptide specific antibodies were obtained both by affinity-purification from malaria immune sera and by immunization of mice and these peptide candidates are used as vaccine candidates for malaria. Malaria peptides that are used as therapeutic purpose are Malaria CSP (334 - 342), Malaria aspartyl proteinase FRET substrate I, MSP - 1 P2, Malaria merozoite surface peptide – 1, peptides from circumsporozoite (CS) Protein, hemoglobin, 3037a etc. 3,4,5,6.

Structural Characteristics
These are smaller peptides of different sizes. The sequence of Malaria CSP (334 - 342) is H - Tyr - Leu - Lys - Lys - Ile - Lys - Asn - Ser - Leu – OH. MSP - 1 P3, Malaria Merozoite Surface Peptide – 1 sequence is H - Lys - Leu - Asn - Ser - Leu - Asn - Asn - Pro - His - Asn - Val - Leu - Gln - Asn - Phe - Ser - Val - Phe - Phe - Asn - Lys – OH. The amino acid sequence of Hemoglobin, 3037a, Malaria FRET Substrate II—is DABCYL - GABA - Glu - Arg - Met - Phe - Leu - Ser - Phe - Pro – EDANS. The immunodominant T cell epitope of the merozoite antigen ring-infected erythrocyte surface antigen sequence is H-Leu-Gly-Arg-Ser-Gly-Gly-Asp-Ile-Ile-Lys-Lys-Met-Gln-Thr-Leu-OH 3,4,5,6.

Mode of Action
Malaria peptides has been shown to accelerate the humoral antibody immune responses and as a free peptide increase the protective efficacy of cellular immune response and sustain the immunity for a longer time against malaria A. Peptides copying malaria protein sequences often stimulate human CD4+ T cells and it was thought that they represented T cell epitopes present in the parasite and may thus have particular relevance to malaria vaccine development. A 15 residue peptide (PP1) inhibited falcipain-2 enzyme of Plasmodium falciparum activity in vitro. PP1 fused with Antennapedia homeoprotein internalization domain blocked hemoglobin hydrolysis, merozoite release and markedly inhibited Plasmodium falciparum growth and maturation 7. A peptide derived from the proregion of falcipain-2 that blocks late-stage malaria parasite development in RBCs, suggesting the development of peptide and peptidometric drugs against the human malaria parasite 2.

Functions

Malaria CSP (334 - 342) - This is amino acids 334 to 342 fragment of malaria CSP derived from malaria circumsporozoite protein. It is commonly used as a control peptide for melanoma vaccine studies 8.

Malaria Aspartyl Proteinase FRET Substrate I- A useful fluorogenic substrate for the continuous assay of malaria aspartyl proteinase.


MSP - 1 P2, Malaria Merozoite Surface Peptide - 1- This peptide is a fragment of malaria Merozoite Protein 1, MSP-1 (codons 250–271), a malaria vaccine candidate designated P2. It is used to assess T cell response to N-terminal region of MSP-1 4.


MSP - 1 P3, Malaria Merozoite Surface Peptide - 1-This N-terminal region fragment of Malaria, Merozoite Surface Protein (codons 1101–1121), is a malaria vaccine candidate designated as P3. It is used to assess T cell response to the N-terminal region of major merozoite surface protein 1 (MSP-1).

 

Hemoglobin, 3037a, Malaria FRET Substrate II- The sequence of this peptide is based on the primary site of cleavage within hemoglobin (Hb). This peptide was used to characterize the molecular mechanism underlying Hb degradation by plasmepsin II (PM II). N-terminal (GABA) extension results in higher maximal velocity and dramatic concentration-dependent substrate inhibition 5.


Circumsporozoite (CS) Protein Sequence-This cell-adhesive motif in region II of malarial circumsporozoite protein has also been found in thrombospondin, properdin, and in a blood-stage antigen of Plasmodium falciparum. It was shown to be the critical sequence for the observed cell-adhesive properties 9.


RESA Peptides-This peptide is identical to the immunodominant T cell epitope of the merozoite antigen ring-infected erythrocyte surface antigen Pf155/RESA in its nonrepeated amino-terminal region (residues 181-195) 10.

Malaria Aspartyl Proteinase Substrate- Useful peptide substrate for a continuous fluorescence-based assay of the malaria aspartyl proteinase. The peptide sequence is derived from the cleavage site present in haemoglobin 11.

References

1.     Moorthy VS, Good MF, Hill AV (2004). Malaria vaccine developments. Lancet., 363(9403):150-156.

2.     Scanlon D, Harris KS, Coley AM, Karas JA, Casey JL, Hughes AB, Foley M (2008). Comprehensive N-Methyl Scanning of a Potent Peptide Inhibitor of Malaria Invasion into Erythrocytes Leads to Pharmacokinetic Optimization of the Molecule. International Journal of Peptide Research and Therapeutics, 14(4):381-386.

3.     Yamshchikov GV, Mullins DW, Chang CC, Ogino T, Thompson L, Presley J, Galavotti H, Aquila W, Deacon D, Ross W, Patterson JW, Engelhard VH, Ferrone S, Slingluff CL Jr. (2005). Sequential immune escape and shifting of T cell responses in a long-term survivor of melanoma. J Immunol., 174(11):6863-6871.

4.     King CL, Malhotra I, Wamachi A, Kioko J, Mungai P, Wahab SA, Koech D, Zimmerman P, Ouma J, Kazura JW.(2002). Acquired immune responses to Plasmodium falciparum merozoite surface protein-1 in the human fetus. J. Immunol., 168(1):356-64.

5.     Istvan E, Goldberet D (2005). Distal Substrate Interactions Enhance Plasmepsin Activity. The Journal of Biological Chemistry, 280:6890-6896.

6.     Savi P, Bernat A, Lalé A, Roque C, Zamboni G, Herbert JM (2000). Effect of aspirin on platelet desaggregation induced by SR121566, a potent GP-IIb/IIIa antagonist. Platelets, 11(1):43-48

7.     Korde R, Bhardwaj A, Singh R, Srivastava A, Chauhan VS, Bhatnagar RK, Malhotra P (2008). A prodomain peptide of plasmodium falciparum cysteine protease(falcipain-2) inhibits malaria parasite development. J. Med. Chem., 51(11): 3116–3123.

8.     Blum-Tirouvanziam U, Servis C, Habluetzel A, Valmori D, Men Y, Esposito F, Del Nero L, Holmes N, Fasel N, Corradin G (1995). Localization of HLA-A2.1-restricted T cell epitopes in the circumsporozoite protein of Plasmodium falciparum. J. Immunol., 154(8):3922-3931.      

9.     Flotow H, Leong CY, Buss AD (2002). Development of a plasmepsin II fluorescence polarization assay suitable for high throughput antimalarial drug discovery. J Biomol Screen., 7(4):367-371.

10.  Chougnet C, Troye-Blomberg M, Deloron P, Kabilan L, Lepers JP, Savel J, Perlmann P (1991). Human immune response in Plasmodium falciparum malaria. Synthetic peptides corresponding to known epitopes of the Pf155/RESA antigen induce production of parasite-specific antibodies in vitro. J. Immunol., 147(7):2295-2301.

11.  Jiang S, Prigge ST, Wei L, Gao Ye, Hudson TH, Gerena L, Dame JB, Kyle DE (2001). New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins. Antimicrob Agents Chemother., 45(9):2577-2584.

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