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. Mosquitoes transmit the Plasmodium parasite from infected human hosts to uninfected individuals. By blocking a critical protein-glycan (carbohydrate) interaction between the parasite and the mosquito vector through the use of small inhibitory compounds (drugs) we prevent parasite establishment in the mosquito and effectively disrupt the transmission cycle of the malaria parasite. This strategy is especially important given that many current antimalarials and vaccine candidates still permit transmission of the parasite through the mosquito, moreover, our lead compound has added potential utility as a multi-stage antimalarial therapeutic since it also prevents sporozoite establishment in liver cells, the first step towards the progression of disease in humans.

Public Health Relevance

Mosquitoes transmit the Plasmodium parasite from infected human hosts to uninfected individuals. By blocking a critical protein-glycan (carbohydrate) interaction between the parasite and the mosquito vector through the use of small inhibitory compounds (drugs) we prevent parasite establishment in the mosquito and effectively disrupt the transmission cycle of the malaria parasite. This strategy is especially important given that many current antimalarials and vaccine candidates still permit transmission of the parasite through the mosquito, moreover, our lead compound has added potential utility as a multi-stage antimalarial therapeutic since it also prevents sporozoite establishment in liver cells, the first step towards the progression of disease in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI082587-04
Application #
8237055
Study Section
Special Emphasis Panel (ZAI1-GSM-M (J3))
Program Officer
Costero, Adriana
Project Start
2009-04-22
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$401,841
Indirect Cost
$156,816
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ruecker, A; Mathias, D K; Straschil, U et al. (2014) A male and female gametocyte functional viability assay to identify biologically relevant malaria transmission-blocking drugs. Antimicrob Agents Chemother 58:7292-302
Armistead, Jennifer S; Morlais, Isabelle; Mathias, Derrick K et al. (2014) Antibodies to a single, conserved epitope in Anopheles APN1 inhibit universal transmission of Plasmodium falciparum and Plasmodium vivax malaria. Infect Immun 82:818-29
Mathias, Derrick K; Jardim, Juliette G; Parish, Lindsay A et al. (2014) Differential roles of an Anopheline midgut GPI-anchored protein in mediating Plasmodium falciparum and Plasmodium vivax ookinete invasion. Infect Genet Evol 28:635-47
Bruno, Michela; Trucchi, Beatrice; Monti, Diego et al. (2013) Synthesis of a potent antimalarial agent through natural products conjugation. ChemMedChem 8:221-5
Parish, Lindsay A; Colquhoun, David R; Ubaida Mohien, Ceereena et al. (2011) Ookinete-interacting proteins on the microvillar surface are partitioned into detergent resistant membranes of Anopheles gambiae midguts. J Proteome Res 10:5150-62