Metal Coordination Compounds as Reporters for Biological NO

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Nitric oxide (NO) is an important molecule that controls many biological processes including smooth muscle dilation in the heart and other organs, neurotransmission, and functioning of the immune system. Through this award, funded by the Chemical Structure, Dynamics, and Mechanisms B Program of the Division of Chemistry, Professor Stephen J. Lippard from the Massachusetts Institute of Technology will investigate the chemistry of nitric oxide with transition metal complexes that can be incorporated into novel, peptide-based, platforms for its detection as a signaling agent in biology. This project investigates these roles through the preparation and application of bright, light-emitting molecules based on transition metal chemistry to track the generation and translocation of nitric oxide to its biological targets. Several of these targets include transition metals centers, and the chemistry by which they respond to NO is another subject of investigation. By directing the sensors to specific cellular locales, such as the cell membrane or organelles like the mitochondrion, spatiotemporal information about NO as a signal transduction molecule can be obtained by fluorescence microscopic studies. Reactive species derived from NO, specifically HNO (nitroxyl) and HSNO (nitrosothiol), will also be investigated. Through chemistry, the probes will be made selective for NO, HNO, or HSNO, kinetically tuned for rapid turn-on, ratiometric to allow for quantitation, reversible, and able to emit at low energies to minimize unwanted background. The chemical dynamics and mechanisms discovered during the design and implementation of the sensors may have parallels in living systems and thereby enrich our knowledge of how transition metal centers respond to nitric oxide and its derivatives. Peptides provide an excellent platform for incorporating units to localize the sensors to subcellular locales, a great advantage for studying functions in live cells and tissue slices. Applications ranging from the design of antibiotics to the determination of the roles of nitric oxide in sensory perception can be envisioned. These projects will continue the training of young scientists in chemistry. Graduate and postdoctoral researchers on the project are also mentors to undergraduate research opportunity participants (UROPs) at MIT. These scientists are encouraged to communicate their work both orally and in writing. Many subsequently assume key positions in academic or industrial organizations and some are active in outreach programs at schools in the local communities.