Friday, November 22, 2024
11/22/2024
Project Summary/Abstract Reactive sulfur species (RSS), including hydrogen sulfide (H2S), persulfides (RSSH), and polysulfides (RSSnR, n>1), are endogenously expressed biomolecules that play an important role in human health and disease. For example, the biological activity of the most prominent member of this class of compounds, H2S, has been shown to include anticancer activity, neuroprotection, vascular relaxation, hormonal regulation, and energy production. Given these effects, it comes as no surprise that RSS supplementation is being explored with great interest in preclinical models of human illnesses, including cancer, Parkinson’s and Alzheimer’s disease, cardiovascular- related pathologies, and other age-related illnesses. However, due to their high reactivity and short half-life, the effective delivery and detection of RSS is extremely challenging. Thus, RSS have untapped potential when it comes to the diagnosis and treatment of disease. In a similar fashion, reactive selenium species (RSeS), such as hydrogen selenide (H2Se) and hydroselenosulfides (RSeSH and RSSeH), have begun to attract significant attention from the chemical biology and medicinal chemistry communities due to their purported therapeutic properties. However, the biological activity of these selenium congeners is not well documented due to similar inadequacies when it comes to their delivery and detection. Therefore, the work described in this proposal is significant as it seeks to overcome these barriers by implementing new and innovative chemistry that will harness the reactivity of RSS and RSeS to help realize the biomedical applicability of these molecules for both the development of novel therapeutics, including small molecule donors (or RSS/RSeS releasing compounds) with improved properties (organelle-targeting, pathology-selective activation, self-reporting features for monitoring donor progress and trafficking, and novel co-drug designs for improved activity and/or chemoprotective effects) and diagnostics (reaction-based fluorescent sensors and RSS/RSeS-triggered theranostics). This contribution will be innovative as it is expected to open the door to new approaches for therapeutic intervention involving both RSS and RSeS.
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