title: Binding hot spot for invasion inhibitory molecules on Plasmodium falciparum apical membrane antigen 1.
abstract: Apical membrane antigen 1 (AMA1) is expressed in schizont-stage malaria parasites and sporozoites and is thought to be involved in the invasion of host red blood cells. AMA1 is an important vaccine candidate, as immunization with this antigen induces a protective immune response in rodent and monkey models of human malaria. Additionally, anti-AMA1 polyclonal and monoclonal antibodies inhibit parasite invasion in vitro. We have isolated a 20-residue peptide (R1) from a random peptide library that binds to native AMA1 as expressed by Plasmodium falciparum parasites. Binding of R1 peptide is dependent on AMA1 having the proper conformation, is strain specific, and results in the inhibition of merozoite invasion of host erythrocytes. The solution structure of R1, as determined by nuclear magnetic resonance spectroscopy, contains two structured regions, both involving turns, but the first region, encompassing residues 5 to 10, is hydrophobic and the second, at residues 13 to 17, is more polar. Several lines of evidence reveal that R1 targets a "hot spot" on the AMA1 surface that is also recognized by other peptides and monoclonal antibodies that have previously been shown to inhibit merozoite invasion. The functional consequence of binding to this region by a variety of molecules is the inhibition of merozoite invasion into host erythrocytes. The interaction between these peptides and AMA1 may further our understanding of the molecular mechanisms of invasion by identifying critical functional regions of AMA1 and aid in the development of novel antimalarial strategies.
authors.affiliation: Department of Biochemistry, La Trobe University, Victoria, Australia.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Harris
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Casey
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Coley
authors.forename: Rosella
authors.initials: R
authors.lastname: Masciantonio
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Sabo
authors.forename: David W
authors.initials: DW
authors.lastname: Keizer
authors.forename: Erinna F
authors.initials: EF
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: McMahon
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.forename: Michael
authors.initials: M
authors.lastname: Foley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001681:Biological Assay; D002352:Carrier Proteins / Q000737:chemistry / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D019151:Peptide Library; D010963:Plasmodium falciparum / Q000187:drug effects*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000953:Antigens, Protozoan; D000962:Antimalarials; D002352:Carrier Proteins; D008565:Membrane Proteins; D019151:Peptide Library; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium; C505467:peptide R1