Establishing Sts-1 as a Novel Target to Treat Deadly Pathogen Infections
Technical Report,15 May 2017,14 Nov 2018
Research Foundation for the State University of New York Stony Brook United States
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This proposal addresses a unique approach to improving clinical outcomes for individuals who have contracted life-threatening bacterial and fungal infections. Two homologous phosphatases, Sts-1 and Sts-2, have been established as negative regulators of signaling pathways within mammalian immune cells. Experimental mice in which the Sts proteins are functionally inactivated have been shown to be profoundly resistant to infection with high doses of different microbial pathogens, including Candida albicans, Francisella tularensis LVS, and Staphylococcus aureus. Resistance was characterized by an altered immune response and enhanced pathogen clearance. We propose to develop pharmacological inhibitors of Sts-1, in order to enhance anti-microbial immune responses. Proposed Aims are to 1 determine how leukocyte anti-microbial effector functions are regulated by Sts-1 activity 2 conduct a 20,000 compound pilot screen for Sts-1 inhibitors 3 solve X-ray crystal structures of Sts-1-drug complexes to characterize the active site architecture and 4 assess how HTS lead compounds alter leukocyte microbicidal responses and survival curves following infection. The Major Accomplishments are as follows 1 identification of ROS production in bone marrow-derived dendritic cells as a major target of regulation by the Sts proteins. ROS is an important phagocyte anti-microbial effector mechanism 2 identification of the IFNgamma signaling pathway in marrow-derived monocytes as a target of Sts regulatory activity 3 established feasibility of selectively inhibiting Sts-1 by identified two classes of inhibitors tetracyclines and azo dyes 4 obtained a high resolution x-ray crystallographic structure human Sts-1 histidine phosphatase domain 5 developed assay to assess inhibition of Sts-1 within cells.
- Medicine and Medical Research