Small Molecule Protein-Glycan Inhibitors as Malaria Transmission-Blocking Therapeutics
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Malaria transmission entails development of the Plasmodium parasite in the mosquito. We have identified a critical interaction between an unknown ookinete lectin-like protein and a chondroitin sulfate glycosaminoglycan ligand on the mosquito midgut lumenal surface. We hypothesize that by disrupting this interaction through the use of small molecule inhibitors we can prevent parasite establishment in the mosquito and, subsequently, completely abrogate malaria transmission. This is a translational research grant proposal with the goal of taking our basic research understanding of Plasmodium-mosquito host interactions toward the development of novel highly potent malaria transmission-blocking therapeutics. Our first aim, the Complete molecular characterization of Plasmodium ookinete protein-midgut glycosaminoglycan interactions involves (1) identifying novel lectin-like ookinete molecules by glycan-affinity chromatography and mass spectrometry, (2) characterizing their functional role in vivo through the production of gene knockout parasites, (3) assessing their binding affinity for mosquito chondroitin glycosaminoglycans by protein array-surface plasmon resonance, and (3) gaining insight into the structure-function of the molecule(s) in complex with chondroitin glycosaminoglycan fragments and structural analogues by molecular modeling and x-ray crystallography. The second aim of the project, the Development of lead Plasmodium transmission-blocking glycan-mimetic compounds and assessment of their transmission-blocking potential involves identification of novel derivatives and analogues of our lead transmission-blocking compound, VS1 (a non-peptidyl polyvinylsulfonated polymer), which is a structural mimic of midgut chondroitin glycosaminoglycans and inhibits >95% of parasite development in the
mosquito. To develop more potent structural analogs, we propose a four-tiered approach: (1) isolation of varying chain-lengths of the VS1 polymer, (2) derivitization of VS1 to enhance inhibitory activity and bioavailability, (3) derivitization of (+)-usnic acid, a polyphenolic compound from lichens, and (4) assessment of the utility of peptide mimotopes of mosquito chondroitin sulfate glycosaminoglycans as transmission-blocking vaccine targets. To
help progress toward preclinical studies, the top candidate compounds from each approach will be analyzed for their pharmacokinetic and pharmacodynamic properties in animal and human serum models.
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