, based on our prior published work as well as the new studies presented, we anticipate that this Scientific Core will be highly interactive with each of the projects in the HMS/UC Center for Cyanide Countermeasure Discovery and Development. The main goal of the metabolomics platform will be to progress compounds along the therapeutic development pathway, preliminary studies already highlight how the technologies we have implemented can provide additional scientific value. Specific interactions will include: Project 1: This project serves as the discovery engine that will generate numerous unrefined chemical hits. Identifying which hits merit further optimization will be facilitated by the metabolomics core. Metabolic profiling will help us identify distinct patterns by which compounds ameliorate cyanide's toxicities. This information ensures that a diverse group of molecules and mechanisms are represented among the countermeasures that we maintain in our pipeline. The ability to intervene along multiple distinct pathways will likely provide synergistic therapeutic outcomes. In addition, we will also assess the metabolic responses to cyanide in discrete vulnerable states, with the goal of refining the pathways responsible for sensitivity or resistance to cyanide exposure. This effort may generate candidate biomarkers for such vulnerable stares. Project 2: This project serves as a bridge between discovery and mammalian efficacy testing. As in Project 1, prioritization of these optimized compounds will benefit from a more precise understanding of their metabolic roles. In addition, the Core will allow us to assess initial DMPK attributes of compounds under study. Project 3: This project represents the final evaluation of compounds that we will nominate for human intervention. As in the first two projects, the platform will provide insight into mechanism(s) of action, but in this case as we move to mammalian species. Furthermore, because the platform is sensitive to pharmacological perturbations, studies of countermeasures in mammalian species may help us judge their relative safety and potential off-target effects. Embedded within our studies of interventions are clear opportunities to identify new diagnostic markers both of cyanide intoxication itself as well as effective rescue. Finally, a more complete understanding of the broad spectrum of metabolic derangements secondary to cyanide toxicity may highlight specific enzymes that might be therapeutic targets or metabolites that themselves may be used as therapeutic interventions.
| Sips, Patrick Y; Shi, Xu; Musso, Gabriel et al. (2018) Identification of specific metabolic pathways as druggable targets regulating the sensitivity to cyanide poisoning. PLoS One 13:e0193889 |
| Nath, Anjali K; Shi, Xu; Harrison, Devin L et al. (2017) Cisplatin Analogs Confer Protection against Cyanide Poisoning. Cell Chem Biol 24:565-575.e4 |
| MacRae, Calum A; Boss, Gerry; Brenner, Matthew et al. (2016) A countermeasure development pipeline. Ann N Y Acad Sci 1378:58-67 |
| MacRae, Calum A; Peterson, Randall T (2015) Zebrafish as tools for drug discovery. Nat Rev Drug Discov 14:721-31 |
| Palchaudhuri, Rahul; Lambrecht, Michael J; Botham, Rachel C et al. (2015) A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed. Cell Rep 13:2027-36 |
| MacRae, Calum A (2015) A new phenotypic lexicon for accelerated translation: rise of the machines. Circulation 131:234-6 |
| Burns, Andrew R; Luciani, Genna M; Musso, Gabriel et al. (2015) Caenorhabditis elegans is a useful model for anthelmintic discovery. Nat Commun 6:7485 |
| Buys, Emmanuel; Sips, Patrick (2014) New insights into the role of soluble guanylate cyclase in blood pressure regulation. Curr Opin Nephrol Hypertens 23:135-42 |
| Jackson, Randy; Oda, Robert P; Bhandari, Raj K et al. (2014) Development of a fluorescence-based sensor for rapid diagnosis of cyanide exposure. Anal Chem 86:1845-52 |
| Musso, Gabriel; Tasan, Murat; Mosimann, Christian et al. (2014) Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish. Development 141:224-35 |
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