Novel Triazole-Adenosine Conjugates as Mammalian Seryl-tRNA Synthetase Inhibitors to protect cells from Ischemia-Reperfusion Injury
Abstract
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.
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BibTeX
@article{simon2026novel,
title = {{Novel Triazole-Adenosine Conjugates as Mammalian Seryl-tRNA Synthetase Inhibitors to protect cells from Ischemia-Reperfusion Injury}},
author = {Lauriane Simon and Audrey Di Giorgio and Marc Cougnon and Michel Tauc and Didier Pisani and Maria Duca},
journal = {RSC Medicinal Chemistry},
year = {2026},
month = sep,
doi = {10.1039/d6md00593d},
url = {https://hal.science/hal-05777964v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Novel Triazole-Adenosine Conjugates as Mammalian Seryl-tRNA Synthetase Inhibitors to protect cells from Ischemia-Reperfusion Injury
AU - Lauriane Simon
AU - Audrey Di Giorgio
AU - Marc Cougnon
AU - Michel Tauc
AU - Didier Pisani
AU - Maria Duca
PY - 2026
DA - 2026/09/10
JO - RSC Medicinal Chemistry
DO - 10.1039/d6md00593d
UR - https://hal.science/hal-05777964v1
AB - 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.
SN - 2632-8682
ER -