Posted May 25, 2016
Mary Ann McDowell, Ph.D., University of Notre Dame

With funding support from the Department of Defense (DoD), Dr. McDowell is identifying new targets within shared pathways of disease vectors, while moving novel targets into the screening and optimization phases.

Vector-borne diseases like malaria and leishmaniasis continue to threaten the health of U.S. Service members operating in parts of the world where these diseases are endemic. Malaria is caused by the parasitic protozoan Plasmodium, which is transmitted via the bite of a female Anopheles mosquito. A total of 1021 malaria cases were reported in U.S. Service members just in the past 10 years. Beyond military cases, 3 million deaths and up to 500 million acute clinical cases are reported each year.

For malaria, Food and Drug Administration-approved drugs have decreased utility due to the rapid emergence of drug-resistant strains. Due to these resistance strains, current antimalarial drugs are capped for use at 6 months. Insect management has demonstrated success in limiting transmission of diseases like malaria, but unfortunately, insect management has been limited by resistance to insecticide treatment and toxicity in humans.

Dr. Mary Ann McDowell of Notre Dame's Eck Institute for Global Health focuses on two vector-transmitted, intracellular parasites: Leishmania and Plasmodium. Using a combinatorial approach of laboratory models and field-based studies, her research investigates immunology, host cell-biology, pathogen diversity, and insect vector biology to further characterize the roles of novel targets. Dr. McDowell utilizes insect-vector genome data and high-throughput screening approaches to screen and identify novel compounds with low human toxicity that kill or repel mosquitoes, even those resistant to traditional insecticides.

With this DoD award, Dr. McDowell's team has begun to identify targets for new broad range insecticides that are safe for human use. Her research priority is to identify lead compounds that will be further developed as public health insecticides. Dr. McDowell's team is focusing on G-protein coupled receptors (GPCRs) as targets of insecticide-discovery, particularly octopamine receptors (OAR) whose functions include neuromodulation. GPCRs are highly attractive targets because they play various roles in essential insect functions and are highly “druggable.” Computational modeling, protein confirmation, and in silico docking experiments that scan small molecule libraries to predict high-priority chemistries have produced relevant interactions for OARs. Dr. McDowell's team has developed OAR agonist analogs that are comparable to other insecticides, such as Amitraz and Permethrin.

Next, Dr. McDowell will further optimize promising chemistries for developing insecticides including modifications to enhance stability, reduce human toxicity, and increase effectiveness. Furthermore, private–public partnerships will be initiated, and promising targets will be made available to industry partners for further screening and development. The project has yielded a computational pipeline for detecting and ranking GPCRs in a genome-wide fashion and expressed sequence tag analysis of two species of mosquito.

Publications:

Kastner KW, Shoue DA, Estiu GL, et al. 2014. Characterization of the Anopheles gambiae octopamine receptor and discovery of potential agonists and antagonists using a combined computational-experimental approach. Malaria Journal 13:434.

Nowling RJ, Abrudan JL, Shoue D, Abdul-Wahid B, et al. 2013. Identification of novel arthropod vector G protein-coupled receptors. Parasites & Vectors 6:150.

Abrudan J, Ramalho-Ortigão M, O'Neil S, et al. 2013. The characterization of the Phlebotomus papatasi transcriptome insect. Mol Biol. 22(2):211-232.

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