Local anesthetics(LAs),such as articaine(AT),exhibit limited efficacy in inflammatory environments,which constitutes a significant limitation in their clinical application within oral medicine.In our prior research,we...Local anesthetics(LAs),such as articaine(AT),exhibit limited efficacy in inflammatory environments,which constitutes a significant limitation in their clinical application within oral medicine.In our prior research,we developed AT-17,which demonstrated effective properties in chronic inflamma-tory conditions and appears to function as a novel oral LA that could address this challenge.In the present study,we further elucidated the beneficial effects of AT-17 in acute inflammation,particularly in oral acute inflammation,where mitochondrial-related apoptosis played a crucial role.Our findings indicated that AT-17 effectively inhibited lipopolysaccharide(LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro.This process involved the inhibition of mitochondrial reactive oxygen species(mtROS)production and the subsequent activation of the NRF2 pathway.Most notably,improve-ments in mitochondria-related apoptosis were key contributors to AT-17’s inhibition of voltage-gated sodium channels.Additionally,AT-17 was shown to reduce mtROS production in nerve cells through the Na+/NCLX/ETC signaling axis.In conclusion,we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis.This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.展开更多
Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmacophores within a singl...Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmacophores within a single-molecule framework.To address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a wellknown local anesthetic.DeepSA integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound generation.This framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent constraints.Through a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models.Mechanistic insights into AT-17 revealed its dual mode of action:selective inhibition of NaV1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway.These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.展开更多
基金supported by the National Natural Science Foun-dation of China(82425054 and 82273784)the Research and Develop Program,West China Hospital of Stomatology Sichuan University(RD-03-202004,China)+6 种基金Health Commission of Sichuan Province Medical Science and Technology Program(No.24CGZH05,China)the 1.3.5 Projects for Disciplines of Excel-lence,West China Hospital,Sichuan University(ZYGD25002 and ZYGD23025,China)the Sichuan Science and Technology Pro-grams(2024NSFSC0048,2023ZYD0168,2024YFFK0374 and 2023ZYD0168,China)the National Natural Science Foundation of China(82425054 and 82273784)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD25002 and ZYGD23025,China)Nature Science Foundation of Sichuan Province(2024NSFSC0048,China)Sichuan Science and Technology Program(2023ZYD0168,China).
文摘Local anesthetics(LAs),such as articaine(AT),exhibit limited efficacy in inflammatory environments,which constitutes a significant limitation in their clinical application within oral medicine.In our prior research,we developed AT-17,which demonstrated effective properties in chronic inflamma-tory conditions and appears to function as a novel oral LA that could address this challenge.In the present study,we further elucidated the beneficial effects of AT-17 in acute inflammation,particularly in oral acute inflammation,where mitochondrial-related apoptosis played a crucial role.Our findings indicated that AT-17 effectively inhibited lipopolysaccharide(LPS)-induced nerve cell apoptosis by ameliorating mitochondrial dysfunction in vitro.This process involved the inhibition of mitochondrial reactive oxygen species(mtROS)production and the subsequent activation of the NRF2 pathway.Most notably,improve-ments in mitochondria-related apoptosis were key contributors to AT-17’s inhibition of voltage-gated sodium channels.Additionally,AT-17 was shown to reduce mtROS production in nerve cells through the Na+/NCLX/ETC signaling axis.In conclusion,we have developed a novel local anesthetic that exhibits pronounced anesthetic functionality under inflammatory conditions by enhancing mitochondria-related apoptosis.This advancement holds considerable promise for future drug development and deepening our understanding of the underlying mechanisms of action.
基金supported by the National Natural Science Foundation of China(82273784,China)the Research and Develop Program,West China Hospital of Stomatology Sichuan University(RD-03-202004,China)+3 种基金the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC 21002,ZYGD23025,China)the Clinical Research Innovation Project,West China Hospital,Sichuan University(2019 HXCX006,China)the Science and Technology Major Project of Tibetan Autonomous Region of China(XZ202201ZD0001G,China)the Sichuan Science and Technology Program(2023 ZYD0168,China).
文摘Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects.The primary challenge is to integrate diverse pharmacophores within a single-molecule framework.To address this,we introduced DeepSA,a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine,a wellknown local anesthetic.DeepSA integrates deep neural networks into metaheuristics,effectively constraining molecular space during compound generation.This framework employs a sophisticated objective function that accounts for scaffold preservation,anti-inflammatory properties,and covalent constraints.Through a sequence of local editing to navigate the molecular space,DeepSA successfully identified AT-17,a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models.Mechanistic insights into AT-17 revealed its dual mode of action:selective inhibition of NaV1.7 and 1.8 channels,contributing to its prolonged local anesthetic effects,and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway.These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery,particularly within stringent chemical constraints.
