Discovery of a novel quinoxaline derivative modulator via a dual P53/TLR2 targeting strategy for the alleviation of radiation damage

With the development of nuclear technology, the risk of people being exposed to nuclear radiation is increasing. So the development of efficient and safe radiation protection agents for nuclear emergencies is urgent. In this study, a series of novel quinoxaline molecules were designed and synthesized with Ex-RAD and TLR2 Agonist as the lead, showing anti-radiation effects and compound Z9 was the best one of them. Our work indicated that Z9 emerged as a potent dual modulator targeting both TLR2 and P53 pathway, remarkably preventing the radiation-induced death in mice with the survival rate of 100 %. In the same time, Z9 had significant radioprotection of the haematopoietic system and intestinal villi in mice. In addition, Z9 significantly reduced radiation-induced Apoptosis, DNA damage, P53 and Bax expression of AHH-1, while Z9 up-regulated the expressions of TLR2 downstream proteins MyD88 and P65 of HUVECs. Notably, Z9 showed excellent stability and affinity for the TLR2 protein conjugate in molecular docking and molecular dynamics simulations. These findings suggested that Z9 was worth further research being a potential candidate for anti-radiation drugs, as the dual modulator of P53/TLR2.

DNA damage Multitargeted drugs; P53 apoptotic pathway; Radioprotective; TLR2.