Generation and Solution of Reactivity of Nitroxyl (HNO)

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The Chemical Structure, Dynamics, and Mechanism Program supports Professor John P. Toscano of the Chemistry Department at Johns Hopkins University for research involving the generation and solution reactivity of nitroxyl (HNO), which has recently received significant attention, especially as a potential alternative to current treatments of cardiac failure. Due to its inherent reactivity, HNO must be generated in situ, but only a very limited number of appropriate precursors currently exist. Adding to the difficulty of studying HNO chemistry is that a viable method for its direct detection in solution or biologically relevant preparations is not currently available. The proposed research will address these current deficiencies in the understanding of HNO chemistry and biochemistry, in available HNO donor molecules, and in practically useful direct HNO detection techniques. In particular, research will develop (1) new precursors to HNO as well as (2) new analytical approaches for the detection and study of HNO focusing on membrane inlet mass spectrometry (MIMS). In addition, research will also address the HNO-induced modifications of the protein phospholamban (PLN), which is involved in regulating the cardiac sarcoplasmic reticulum calcium pump (SERCA2a), to determine the mechanism by which HNO enhances SERCA2a activity.The development of new HNO donors, combined with reactivity studies and the evaluation of HNO-induced protein modifications, will not only provide fundamental insight into the biological activity of HNO, but may also ultimately lead to the development of a new class of compounds for the treatment of heart failure. In addition, proposed research on the development of new precursors to HNO, new analytical tools for its detection, and elucidation of HNO-induced modifications of PLN will afford broad training for graduate students and undergraduates. It will involve the synthesis of the precursors to be studied, careful analysis of reaction mixtures, quantification of products, time-resolved spectroscopic studies, biochemical analyses, and the use of modern analytical techniques. Students will acquire a wide range of skills that will allow them to solve complex problems and will be beneficial for future applications both in industry and academia. Undergraduate participation in research, as well as efforts to broaden the participation of women and underrepresented groups, will continue to be actively encouraged in the current funding period. Undergraduates, either from Johns Hopkins University or nearby universities/colleges with small or no Ph.D. programs, will continue to be involved in research during the academic year and/or over the summer months.