Novel triazole-adenosine conjugates as mammalian seryl-tRNA synthetase inhibitors to protect cells from ischemia-reperfusion injury.

Aminoacyl-tRNA synthetases (aaRSs) have emerged as multifunctional therapeutic targets beyond their canonical role in protein synthesis. Among them, seryl-tRNA synthetase (SerRS) has been identified as a key regulator of translational stress responses and a promising target for ischemic protection. Building on prior evidence demonstrating that SerRS inhibition confers cytoprotection against anoxia in renal and neuronal cells, we report here the rational design, synthesis, and biological evaluation of a novel series of SerRS inhibitors based on the 5'-adenosine scaffold. First, we showed that the validated seryl-sulfamoyl adenosine (Ser-SA), a stable mimic of the natural l-seryl adenylate intermediate, represented a potent inhibitor of protein translation, likely thanks to inhibition of SerRS, with a very promising protecting effect against ischemia reperfusion injury. To overcome the synthetic limitations of Ser-SA, a new series of nine analogs was designed by replacing the sulfamoyl linker with a 1,2,3-triazole moiety and we demonstrated that this chemical modification preserved the desired biological activity. These results establish triazole-adenosine conjugates as a new chemotype of translation inhibitors with broad cytoprotective activity against I/R injury and support the further development of this scaffold toward optimized anti-ischemic agents.