Prostaglandin E2(PGE2) serves as the ultimate mediator of fever induced by infiammatory factors. In contrast to cyclooxygenase inhibitors that suppress arachidonic acid metabolism, antipyretic herbs possess a well-est...Prostaglandin E2(PGE2) serves as the ultimate mediator of fever induced by infiammatory factors. In contrast to cyclooxygenase inhibitors that suppress arachidonic acid metabolism, antipyretic herbs possess a well-established clinical history in effectively managing fever. However, the specific mechanisms underlying their efficacy remain unclear. Following the screening for lead compounds that inhibit PGE2from antipyretic herbs, alkynylated active molecule probes were designed and synthesized to track and identify potential targets. The target investigation revealed that three antipyretic compounds, namely cinnamaldehyde, 2,4-decadienal, and perillaldehyde, containing α,β-unsaturated aldehyde groups irreversibly targeted the microsomal PGES1-TM4 helix(m PGES1-TM4) at Ser139. This specific interaction effectually inhibited PGE2 production in the cerebral vasculature, leading to exert potent antipyretic effects.α,β-Unsaturated aldehydes targeting m PGES1-TM4 offer a new approach for antipyretic effects with significant potential for various applications.展开更多
Atherosclerosis is a persistent inflammatory state,while vascular endothelial fibrosis is one of the primary causes of atherosclerosis development.Although ligustilide(Lig) was shown to exert obvious antiatherogenic e...Atherosclerosis is a persistent inflammatory state,while vascular endothelial fibrosis is one of the primary causes of atherosclerosis development.Although ligustilide(Lig) was shown to exert obvious antiatherogenic effects in previous studies,its precise mechanism has not been deeply discussed.In this paper,we designed a Lig-derived photoaffinity labelling(PAL) probe to identify potential therapeutic targets of Lig via chemical proteomics approach.Mothers against decapentaplegic homologue 3(SMAD3),a signal transmitter of transforming growth factor-β(TGF-β) which promotes the development of vascular fibrosis,was identified as a potential target of Lig.Lig suppressed the phosphorylation and nuclear translocation of SMAD3 by blocking the interaction between SMAD3 and TGF-β receptor 1,thereby inhibiting the collagen synthesis process.Hence,developing a novel SMAD3 inhibitor may present a promising therapeutic option for preventing vascular fibrosis.展开更多
Multimodal bioorthogonal small molecule probes play a pivotal role in drug-focused biomedical research.However,existing drug tracking and imaging techniques face obstacles in living organisms,hindering precise drug lo...Multimodal bioorthogonal small molecule probes play a pivotal role in drug-focused biomedical research.However,existing drug tracking and imaging techniques face obstacles in living organisms,hindering precise drug localization and target protein capture.Herein,we introduced a multimodal probe named 1-(azidomethyl)pyrene-4,5–dione(AMPD).The probe incorporates adjacent dione structures at the pyrene core.AMPD selectively interacts with oxygen-rich alkene-labeled drug molecules under ice-blue LED light exposure,producing specific fluorescence emission and enabling in vivo tracking and flow cytometry sorting.A methyl azide group was also introduced at the pyrene core to help efficiently enrich target proteins via click chemistry with alkyne-functionalized beads.AMPD demonstrates exceptional biocompatibility,rendering it highly suitable for visual photo-triggered tracking studies.Combined with metabolic labeling using an oxygen-rich alkene-tagged drug molecule probe,AMPD is effective for live animal,tissue,cellular,and in-gel imaging,as well as target protein identification through magnetic capture.With its versatile capabilities,AMPD enhances our comprehension of drug-target interactions at the in vivo level and expedites the process of drug discovery.展开更多
Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species(ROS) production have been associated with aging, cancer,neurodegene...Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species(ROS) production have been associated with aging, cancer,neurodegenerative diseases, and other disorders. Uncoupling protein 2(UCP2) is the effector responsible for regulating cellular thermogenesis and ROS production via dissipating protons in an electrochemical gradient. A UCP2 inhibitor named genipin(GNP) is being researched for its effect on mitochondrial temperature, but little is known about its mechanisms. This study developed several molecular probes to explore the interactions between GNP and UCP2. The result indicated that the hemiacetal structure in GNP could selectively react with the ?-amine of lysine on the UCP2 proton leakage channel through ringopening condensation at the mitochondrial, cellular, and animal levels. A notable feature of the reaction is its temperature sensitivity and ability to conjugate with UCP2 at high fever as lysine-specific covalent inhibitors that prevent mitochondrial thermogenesis. The result not only clarifies the existence of an antipyretic properties of GNP via its irreversible coupling to UCP2, but also reveals a bioorthogonal reaction of hemiacetal iridoid aglycone for selectively binding with the ?-amine of lysine on proteins.展开更多
基金supported by the National Key R&D Program of China (Nos. 2022YFC3500800 and 2022YFC3500805)。
文摘Prostaglandin E2(PGE2) serves as the ultimate mediator of fever induced by infiammatory factors. In contrast to cyclooxygenase inhibitors that suppress arachidonic acid metabolism, antipyretic herbs possess a well-established clinical history in effectively managing fever. However, the specific mechanisms underlying their efficacy remain unclear. Following the screening for lead compounds that inhibit PGE2from antipyretic herbs, alkynylated active molecule probes were designed and synthesized to track and identify potential targets. The target investigation revealed that three antipyretic compounds, namely cinnamaldehyde, 2,4-decadienal, and perillaldehyde, containing α,β-unsaturated aldehyde groups irreversibly targeted the microsomal PGES1-TM4 helix(m PGES1-TM4) at Ser139. This specific interaction effectually inhibited PGE2 production in the cerebral vasculature, leading to exert potent antipyretic effects.α,β-Unsaturated aldehydes targeting m PGES1-TM4 offer a new approach for antipyretic effects with significant potential for various applications.
基金financially supported by National Key Research and Development Program of China(Nos.2018YFC1704800,2018YFC1704805)National Natural Science Foundation of China(No.81673637)the Key R&D Program of Tianjin(No.18YFYZCG00060)。
文摘Atherosclerosis is a persistent inflammatory state,while vascular endothelial fibrosis is one of the primary causes of atherosclerosis development.Although ligustilide(Lig) was shown to exert obvious antiatherogenic effects in previous studies,its precise mechanism has not been deeply discussed.In this paper,we designed a Lig-derived photoaffinity labelling(PAL) probe to identify potential therapeutic targets of Lig via chemical proteomics approach.Mothers against decapentaplegic homologue 3(SMAD3),a signal transmitter of transforming growth factor-β(TGF-β) which promotes the development of vascular fibrosis,was identified as a potential target of Lig.Lig suppressed the phosphorylation and nuclear translocation of SMAD3 by blocking the interaction between SMAD3 and TGF-β receptor 1,thereby inhibiting the collagen synthesis process.Hence,developing a novel SMAD3 inhibitor may present a promising therapeutic option for preventing vascular fibrosis.
基金supported by the National Key Research and Development Program of China(Nos.2022YFC3500800 and2022YFC3500805)。
文摘Multimodal bioorthogonal small molecule probes play a pivotal role in drug-focused biomedical research.However,existing drug tracking and imaging techniques face obstacles in living organisms,hindering precise drug localization and target protein capture.Herein,we introduced a multimodal probe named 1-(azidomethyl)pyrene-4,5–dione(AMPD).The probe incorporates adjacent dione structures at the pyrene core.AMPD selectively interacts with oxygen-rich alkene-labeled drug molecules under ice-blue LED light exposure,producing specific fluorescence emission and enabling in vivo tracking and flow cytometry sorting.A methyl azide group was also introduced at the pyrene core to help efficiently enrich target proteins via click chemistry with alkyne-functionalized beads.AMPD demonstrates exceptional biocompatibility,rendering it highly suitable for visual photo-triggered tracking studies.Combined with metabolic labeling using an oxygen-rich alkene-tagged drug molecule probe,AMPD is effective for live animal,tissue,cellular,and in-gel imaging,as well as target protein identification through magnetic capture.With its versatile capabilities,AMPD enhances our comprehension of drug-target interactions at the in vivo level and expedites the process of drug discovery.
基金supported by the National Natural Science Foundation of China(No.81973449)the National Key Research and Development Program of China(Nos.2018YFC1704800 and 2018YFC1704805)。
文摘Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species(ROS) production have been associated with aging, cancer,neurodegenerative diseases, and other disorders. Uncoupling protein 2(UCP2) is the effector responsible for regulating cellular thermogenesis and ROS production via dissipating protons in an electrochemical gradient. A UCP2 inhibitor named genipin(GNP) is being researched for its effect on mitochondrial temperature, but little is known about its mechanisms. This study developed several molecular probes to explore the interactions between GNP and UCP2. The result indicated that the hemiacetal structure in GNP could selectively react with the ?-amine of lysine on the UCP2 proton leakage channel through ringopening condensation at the mitochondrial, cellular, and animal levels. A notable feature of the reaction is its temperature sensitivity and ability to conjugate with UCP2 at high fever as lysine-specific covalent inhibitors that prevent mitochondrial thermogenesis. The result not only clarifies the existence of an antipyretic properties of GNP via its irreversible coupling to UCP2, but also reveals a bioorthogonal reaction of hemiacetal iridoid aglycone for selectively binding with the ?-amine of lysine on proteins.
