Unmet Need
Cell signaling through hydrogen sulfide (H2S) derivatives is physiologically important and is thought to occur primarily through the generation of hydropersulfides (RSSH) via sulfation of cysteine residues (RSH) on proteins. Moreover, generation of carbonyl sulfide (COS) is known to form H2S through the enzymatic activity of Carbonic Anhydrase (CA), leading to the same downstream production of RSSH. Generation of RSSH has been shown to have cytoprotective effects in the setting of oxidative stress. Development of precursor substrates that mediate the sustained generation of RSSH has been limited by the short half-life of RSSH. Therefore, there is a clear need for long-acting prodrugs that can produce sustained release of RSSH over longer time periods to promote cytoprotective activity.
Technology Overview
Johns Hopkins investigators report that a class of chemicals referred to herein as Alkylamine-Substituted Perthiocarbamates (ASP) act as precursors for the generation of RSSH and COS. The ASP molecules can be tuned appropriately to mediate generation of RSSH and COS over a range of half-lives. Moreover, the described molecules could act as prodrugs and mediate activity in response to external stimuli. The investigators have probed the role of RSSH release, mediated by ASP treatment, in protection of cardiomyocytes in the setting of oxidative stress. In vitro, the administration of ASPs maintains cell viability in the setting of oxidative stress. Furthermore, ASPs show attenuation of injury in a mouse model of myocardial ischemia. Taken together, these results demonstrate the feasibility of prodrug-driven sustained RSSH release and potential downstream cytoprotective benefits in the setting of oxidative stress.
Publication
Khodade VS, Pharoah BM, Paolocci N, Toscano JP. Alkylamine-substituted perthiocarbamates: Dual precursors to hydropersulfide and carbonyl sulfide with cardioprotective actions. Journal of the American Chemical Society. 2020;142(9):4309-4316. http://dx.doi.org/10.1021/jacs.9b12180. doi: 10.1021/jacs.9b12180.
Pharoah, Blaze M et al. “Hydropersulfides (RSSH) Outperform Post-Conditioning and Other Reactive Sulfur Species in Limiting Ischemia-Reperfusion Injury in the Isolated Mouse Heart.” Antioxidants (Basel, Switzerland) vol. 11,5 1010. 20 May. 2022, doi:10.3390/antiox11051010
