Research Progress of Small-Molecular Hydropersulfide Donors

Abstract

The unique chemical structure endowed small-molecular hydropersulfides (RSSH) with unclear but fascinating biological activities, which have been attracted much attention. The donors that could release RSSH smoothly in situ under physiological or pathological conditions will become powerful chemical tools for exploring the physiological functions, mechanism of action, and potential therapeutic benefit of RSSH. Over the past five years, a substantial breakthrough had been achieved in the design and development of RSSH donors, which is summarized in this perspective. According to the activation patterns, the existing donors are divided into five categories, namely esterase-activated donor, ROS (reactive oxygen species)-activated donor, pH-dependent donor, light-activated donor, and nitroreductase-activated donor. All kinds of donors played ideal roles in improving the oxidative stress at the cellular level, part of which also show a positive therapeutic effect in the context of myocardial ischemia-reperfusion injury. Besides, the related release mechanisms and the proof of concept of the donors are briefly introduced. In the next five years, waves of novel donors are emerging. On one hand, diverse donors, with stable and controllable release rate, clear release process, and identified release components, will be designed. On the other hand, the indispensable toolbox of donors will be fully assembled for more in-depth and comprehensive biological activity researches.

In pursuit of feedback activation: New insights into redox-responsive hydropersulfide prodrug combating oxidative stress

“…However, RSSH can be regarded as a reactive metabolite, and therefore its efficient delivery is more preferably achieved through prodrug strategies. In recent years, an array of RSSH prodrugs (also known as RSSH donors or RSSH precursors) have emerged [ [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] ], exhibiting ideal therapeutic effects against pathological processes such as ferroptosis [ 11 , 14 ], ischemia-reperfusion [ 12 , 15 ], paracetamol poisoning [ 37 ], doxorubicin-induced cardiotoxicity [ 13 ] and postoperative pain [ 36 ]. Furthermore, RSSH prodrugs are proven superior to their counterparts, such as H 2 S donors, in terms of antioxidant activity [ 36 ].…”