Drug and Vaccine Targets in Malaria
Targeting the folate pathway enzyme PPPK in malaria
T Louie, G Holloway, J Baell, J Parisot, MC Lawrence, K Lackovic, K Watson
A WEHI high throughput screen, carried out in 2005, made a promising hit with low micromolar activity against the pterin-processing enzyme complex dihydropterin pyrophosphokinase-dihydropteroate synthase (PPPK-DHPS) of the malaria parasite. This was made possible by funding from WHO Tropical Diseases Research. Structure activity relationships (SAR) are being developed through chemical modification of this scaffold in order to assess the potential of developing a new anti-malarial. A small number of these compounds have also been tested by Professor Ian Macreadie at CSIRO showing in vivo inhibition of yeast cultures, confirming their ability to inhibit folate synthesis. Optimisation studies are under way.
Structure and interactions of a malaria surface protein
X Zhang, X Yang, A Low, S Yao, CA MacRaild, RS Norton in collaboration with CG Adda, VJ Murphy, RF Anders (La Trobe University), DC Jackson, MA Perugini (University of Melbourne)
Merozoite surface protein 2 (MSP2) from the malaria parasite Plasmodium falciparum is implicated in erythrocyte invasion and is being developed as a vaccine candidate. The protein is disordered in solution. Peptides from the conserved N-terminal region of MSP2 contain nascent helical and turn-like structures and generate fibrils similar to the amyloid-like fibrils formed by full-length MSP2. NMR resonance assignments for full-length MSP2 define the residual secondary structure and backbone dynamics. Hence, we have identified the region that interacts with the merozoite membrane or with the host red blood cell.