Science, Technology and Engineering

Foley Laboratory

Department of Biochemistry

Malaria

Peptides that bind to malaria antigens and inhibit red blood cell invasion:

A major focus of the lab is to identify small peptide molecules that bind to these proteins and use them as probes of the structure and function of these parasite molecules. Phage peptide libraries are being used in an increasing number of applications and they offer a rapid and efficient means of obtaining short peptides that can act as potential blocking agents in attachment of pathogens to host cells. We have panned these libraries on the malarial surface protein Apical Membrane Antigen (AMA1) and isolated peptides that specifically to this protein. Furthermore these peptides will inhibit the invasion of malaria parasites into the host red blood cells. 

Our aim is now to use these peptides to learn more about the role played by AMA1 in this invasion process and how the peptides are able to inhibit it. Our lab is currently exploring the mechanism by which the peptides inhibit parasite invasion and experiments are planned to construct libraries of mutant peptides to select molecules with improved AMA1 binding and inhibition.

Strategy for selecting peptides that inhibit malaria invasion

Structures of AMA1 binding peptides and peptide mimics of AMA1:

In collaboration with Dr Ray Norton's group (Walter and Eliza Hall Institute for Medical Research, Melbourne, Australia) we are using Nuclear Magnetic Resonance (NMR) to examine the structures of both the peptides that bind directly to AMA1 and those that mimic inhibitory epitopes on this protein. We have identified common secondary structure elements for the AMA1 binding peptides that correlate well with their potency in inhibiting merozoite invasion. The structures provide a valuable starting point for the development of peptidomimetics as anti-malarial antagonists directed at AMA1. In addition we have obtained the first detailed structure of a peptide that mimics an inhibitory epitope on AMA1.

Anti-malarial drug screening by proteome mining:

Given the resistance of P. falciparum to chloroquine and other antimalarial drugs there is a need to develop new drugs to treat the disease. High throughput screening of a small molecule library against ei24 October, 2006tion assay is still time consuming, extremely expensive and importantly do not maximize the full potential of a small molecule library. Furthermore, little information of selectivity, toxicity or mechanism of action is gained. In collaboration with Dr Tim Haysteads group (Duke University, North Carolina, USA) we have used the approach of proteome mining to identify potential drug target in the malaria infected red blood cell. 

Proteome mining allows a large class of functionally important proteins (purine binding proteins) to be interrogated with small molecule libraries, thus providing lead and target identification simultaneously. Furthermore, because all members of the human or Plasmodium purine-binding proteome have an equal opportunity for interacting with a given drug, information on selectivity and potential toxicity can be elucidated. Our work has identified two human enzymes (ALDH1 and QR2) that are selective targets of the quinoline drugs and may provide new insights into the mechanism of action of these drugs.

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