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Biophysical understanding of pathogen-host membrane protein interactions for drug discovery and delivery


Many membrane proteins mediate bacterial pathogenesis and host interactions. These proteins are not themore commonly investigated channels, transporters, and GPCRs and, therefore, provide new knowledge aboutmembrane protein structure, function, and dynamics. Bacterial membrane proteins are targets of antibiotics forwhich resistance is a great threat. In addition, bacterial membrane proteins that interact with hosts haveevolved functions that are attractive to therapeutic delivery technologies (e.g. receptor-mediated uptake). ThisMIRA application outlines our recent endeavors in understanding several different bacterial membraneproteins, as well as, fruitful collaborations bridging biophysics to different biomedical fields. Opa proteins fromNeisseria gonorrhoeae and N. meningitidis are outer membrane proteins that bind to various host receptorsthat induce engulfment of the bacterium. Several of these receptors are overexpressed in cancers and mayprovide a target for therapeutic delivery. Knowledge of the structure, dynamics, and specific interactions of Opaproteins and receptors will be used to design targeted liposome delivery to human cells. We have begun tounderstand the Opa structure and have preliminary data on the interactions between Opa and the receptorCEACAM1. In addition, we have successfully created Opa-liposomes that induce receptor-mediatedphagocytosis. Future directions focus on a multidisciplinary approach to understanding the determinants ofOpa-receptor selectivity and engineer therapeutic delivery liposomes based on the interaction. Anotherfunction of interest to therapeutic delivery, is cellular tracking and controlling cellular fate. IncA, fromChlamydiae, hijacks host trafficking by interacting with host SNAREs allowing the bacterium to avoid lysosomaldegradation. We propose a variety of biophysical and structural approaches to understanding the structure-function relationship of IncA and interactions with itself and SNAREs in order to design intracellular deliverysystems that can avoid lysosomal degradation. Distinct from our research with Opa and IncA, we have begunto investigate potential antibiotic targets to help combat the increase in resistant bacteria. The signal peptidaseII, LspA, is a potential target because it is found in all Gram-negative bacteria and not humans. Globomycinwas isolated and the antibiotic activity was identified in 1978. Although the synthesis and structure are nowknown, globomycin has not become a therapeutic. We aim to explore the binding and inhibition of LspA withglobomycin-like peptides in order to identify viable antibiotics for Gram-negative bacteria. The results of thisproposal with provide unique knowledge and insights about bacterial membrane proteins and their roles inpathogenesis using biophysical approaches and will develop strategies for the design of therapeutics to treatbacterial infections and a variety of human cancers involving CEACAM receptors.

Columbus, Linda M
University of Virginia
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