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The Role Of Phosphorylation And Signalling For Invasion Of Plasmodium Falciparum Into Human Erythrocytes.
Funder
National Health and Medical Research Council
Funding Amount
$307,946.00
Summary
The intracellular signals that govern Plasmodium falciparum malaria invasion of the red blood cell are poorly understood. It is likely calcium dependent phosphorylation leads to recruitment and activation of a cascade of proteins. This study combines a break-through in purification of viable P. falciparum merozoites with proteomic analysis of phosphorylation states to assess intracellular signalling. It is expected the processes identified will be unique to P. falciparum and targetable by drugs.
Use Of Peptides From Phage Display Libraries To Probe The Function Of AMA-1 And Other Malaria Surface Proteins
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is cu ....Malaria remains a major cause of mortality and morbidity worldwide. Much current research is aimed at exploring the molecular interactions between malarial proteins and host components in order to gain a deeper understanding of parasite virulence mechanisms, design alternative anti-malarial approaches and improve vaccine design. The apical membrane antigen-1( AMA-1) is a surface exposed protein which is thought to play a crucial role in invasion of red blood cells by malaria parasites, and is currently one of the leading asexual stage vaccine candidates. While antibodies to AMA-1 prevents malaria invasion, little is known about the role of the antigen in the invasion process. The aim of this proposal is to investigate the molecular interactions that makes AMA-1 an important player in the invasion process. We propose to map the regions of AMA-1 responsible for binding a set of peptides which we have isolated from random peptide libraries. Since these peptides inhibit the invasion of parasites into red blood cells, regions of AMA1- that bind these peptides will be of functional significance. A further outcome will be the identification of peptide residues essential for the inhibition of invasion followed by in vitro evolution of these peptides to improve their binding and inhibitory properties. A molecular description of how AMA1 binding peptides prevent parasite invasion of host erythrocytes will improve our understanding of the invasion process, and aid in improving vaccines based on AMA-1. Furthermore, this peptide-AMA-1 interaction will be assessed as a possible target for the development of novel anti-malarial therapies. Using random peptide libraries we have selected peptides that specifically bind to other merozoite surface proteins thought to be involved in merozoite invasion of erythrocytes. The ability of these peptides to inhibit merozoite invasion will be examined and characterised as described above.Read moreRead less
Signalling During Red Blood Cell Invasion By Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$357,414.00
Summary
Malaria is one of the world's most devastating infectious diseases and is caused by a parasite called Plasmodium falciparum. AMA1 is a parasite surface protein crucial for blood cell invasion but how it works is not understood. We are investigating if AMA1 plays a role in helping the parasite sense when it has contacted a blood cell and should invade. Discovering how parasites attach to and invade bloods cells is a priority for the development of anti-parasite drugs and vaccines
Malaria is a major global health problem. The protein AMA1 plays a key role in the invasion of host cells by malaria parasites, and agents that inhibit this interaction prevent host cell invasion and thus represent leads for the development of anti-malarial drugs. We have identified a number of chemical scaffolds that target a key site on AMA1. In this project we will optimize these leads to generate potent ligands for this site and evaluate the efficacy of these ligands as anti-malarial agents.