The solute carrier family 12(SLC12)of cation-chloride cotransporters(CCCs)comprises potassium chloride cotransporters(KCCs,e.g.KCC1,KCC2,KCC3,and KCC4)-mediated Cl^(-)extrusion,and sodium potassium chloride cotranspor...The solute carrier family 12(SLC12)of cation-chloride cotransporters(CCCs)comprises potassium chloride cotransporters(KCCs,e.g.KCC1,KCC2,KCC3,and KCC4)-mediated Cl^(-)extrusion,and sodium potassium chloride cotransporters(N[K]CCs,NKCC1,NKCC2,and NCC)-mediated Cl^(-)loading.The CCCs play vital roles in cell volume regulation and ion homeostasis.Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues.In recent years,there have been considerable advances in our understanding of CCCs'control mechanisms in cell volume regulations,with many techniques developed in studying the functions and activities of CCCs.Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs.These techniques include the ammonium pulse technique,radioactive or nonradioactive rubidium ion uptakeassay,and thallium ion-uptake assay.CCCs'activity can also be indirectly observed by measuring gaminobutyric acid(GABA)activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes,radiotracer^(36)Cl^(-),and fluorescent dyes.Other techniques include directly looking at kinase regulatory sites phosphorylation,flame photometry,22Nat uptake assay,structural biology,molecular modeling,and high-throughput drug screening.This review summarizes the role of CCCs in genetic disorders and cell volume regulation,current methods applied in studying CCCs biology,and compounds developed that directly or indirectly target the CCCs for disease treatments.展开更多
Cell-free expression systems have emerged as a versatile and powerful platform for metabolic engineering,biosynthesis and synthetic biology studies.Nevertheless,successful examples of the synthesis of complex natural ...Cell-free expression systems have emerged as a versatile and powerful platform for metabolic engineering,biosynthesis and synthetic biology studies.Nevertheless,successful examples of the synthesis of complex natural products using this system are still limited.Bicyclomycin,a structurally unique and complex diketopiperazine alkaloid,is a clinically promising antibiotic that selectively inhibits the transcription termination factor Rho.Here,we established a modular cell-free expression system with cascade catalysis for the biosynthesis of bicyclomycin from a chemically synthesized cyclodipeptide.The six cell-free expressed biosynthetic enzymes,including five iron-andα-ketoglutarate-dependent dioxygenases and one cytochrome P450 monooxygenase,were active in converting their substrates to the corresponding products.The co-expressed enzymes in the cell-free module were able to complete the related partial pathway.In vitro biosynthesis of bicyclomycin was also achieved by reconstituting the entire biosynthetic pathways(i.e.,six enzymes)using the modular cell-free expression system.This study demonstrates that the modular cell-free expression system can be used as a robust and promising platformforthe biosynthesis of complex antibiotics.展开更多
To the Editor:G protein-coupled receptors(GPCRs)are the largest group of membrane proteins with over 800 members,characteristic of a seven transmembrane domain1.By playing crucial roles in regulation of various physio...To the Editor:G protein-coupled receptors(GPCRs)are the largest group of membrane proteins with over 800 members,characteristic of a seven transmembrane domain1.By playing crucial roles in regulation of various physiological processes,GPCRs have been implicated in many diseases including diabetes,obesity,depression and cancer.To initiate different intracellular responses,GPCRs mainly interact with three families of effector proteins upon agonist binding:the heterotrimeric G proteins,G protein-coupled receptor kinases(GRKs)and arrestins1.展开更多
Comprehensive Summary,Valbenazine(Ingrezza),a potent and highly selective inhibitor of vesicular monoamine transporter type 2(VMAT2)through the active metabolite hydrotetrabenazine(HTBZ),has been approved for the trea...Comprehensive Summary,Valbenazine(Ingrezza),a potent and highly selective inhibitor of vesicular monoamine transporter type 2(VMAT2)through the active metabolite hydrotetrabenazine(HTBZ),has been approved for the treatment of tardive dyskinesia and,very recently,for chorea,which is associated with Huntington's disease.Despite numerous synthetic efforts dedicated to the synthesis of HTBZ,the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction.Herein,we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3-dipolar cycloaddition and enzymatic kinetic resolution.The cascade process includes cycloaddition,N—O bond cleavage,and lactamization,which proved to be operationally simple.The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline(THIQ)-fused piperidine in the production of medically significant compounds,such as yohimbine and reserpine.展开更多
Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allo...Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical evaluation.Recently,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge.Here,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i.We also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases.Collectively,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.展开更多
A 61-kb biosynthetic gene cluster(BGC),which is accountable for the biosynthesis of hibarimicin(HBM)B from Microbispora rosea subsp.hibaria TP-A0121,was heterologously expressed in Streptomyces coelicolor M1154,which ...A 61-kb biosynthetic gene cluster(BGC),which is accountable for the biosynthesis of hibarimicin(HBM)B from Microbispora rosea subsp.hibaria TP-A0121,was heterologously expressed in Streptomyces coelicolor M1154,which generated a trace of the target products but accumulated a large amount of shunt products.Based on rational analysis of the relevant secondary metabolism,directed engineering of the biosynthetic pathways resulted in the high production of HBM B,as well as new HBM derivates with improved antitumor activity.These results not only establish a biosynthetic system to effectively synthesize HBMs-a class of the largest and most complex Type-Ⅱpolyketides,with a unique pseudo-dimeric structure-but also set the stage for further engineering and deep investigation of this complex biosynthetic pathway toward potent anticancer drugs.展开更多
Comprehensive Summary This paper presents the first general examples of palladium-catalyzed desulfinative cross-coupling reaction of polyhalogenated aryl triflates with aryl sulfinate salts showing an inversion of the...Comprehensive Summary This paper presents the first general examples of palladium-catalyzed desulfinative cross-coupling reaction of polyhalogenated aryl triflates with aryl sulfinate salts showing an inversion of the conventional reactivity order of C-Br>C-Cl>C-OTf.The catalyst system,comprising of Pd(OAc)_(2)and tBuPhSelectPhos,exhibited excellent catalytic reactivity and chemoselectivity toward this reaction.This reaction had a wide range of substrate scopes and provided a simple and efficient method for the construction of functionalized biaryl motifs.Notably,the C-H···Pd interaction from the methine hydrogen of the C2-cyclohexyl group of the indolyl phosphine ligand with the Pd center may contribute a key factor in reactivity and chemoselectivity.Assisting with density functional theory(DFT)calculations,the results revealed that the oxidative addition step in this reaction was a controlling-chemoselectivity step.展开更多
The control of protein functions with light is valuable for spatiotemporal probing of biological systems.Current small-molecule photo-modulation methods include the light-induced uncaging of inhibitors and chromophore...The control of protein functions with light is valuable for spatiotemporal probing of biological systems.Current small-molecule photo-modulation methods include the light-induced uncaging of inhibitors and chromophore-assisted light inactivation with reactive oxygen species(ROS).However,the constant target protein expression results in inadequate photo-modulation efficiency,particularly for less potent inhibitors and chromophores.Herein,we report a novel bifunctional small-molecule ligands strategy to photo-modulate gene-editing enzymes CRISPR/Cas9.A coumarin-derived small-molecule ligand Bhc-BRD0539 is developed to uncage the active inhibitor upon light irradiation and to generate ROS in the Cas9 proximity for the dual inhibition of Cas9 activity.Our results highlight the synergistic photo-modulation with bifunctional small-molecule ligands,which offers a valuable addition to current CRISPR/Cas9 photo-modulation technologies and may extend to other protein classes.展开更多
The global antibiotic resistance crisis necessitates urgent solutions.One innovative approach involves potentiating antibiotics and non-antibiotic drugs with adjuvants or boosters.A major drawback of these membrane-ac...The global antibiotic resistance crisis necessitates urgent solutions.One innovative approach involves potentiating antibiotics and non-antibiotic drugs with adjuvants or boosters.A major drawback of these membrane-active boosters is their limited biocompatibility,as they struggle to differentiate between prokaryotic and eukaryotic membranes.This study reports the chemical biology investigation of a dual-action oligoamidine(OA1)booster with a glutathione-triggered decomposition mechanism.OA1,when combined with other antimicrobial molecules,exhibits a triple-targeting mechanism including cell membrane disruption,DNA targeting,and intracellular enzyme inhibition.This multi-targeting mechanism not only enhances the in vitro and in vivo eradication of antibiotic-resistant“ESKAPE”pathogens,but also suppresses the development of bacterial resistance.Furthermore,OA1 maintains its activity in bacterial cells by creating an oxidative environment,while it quickly decomposes in mammalian cells due to high glutathione levels.These mechanistic insights and design principles may provide a feasible approach to develop novel antimicrobial agents and effective anti-resistance combination therapies.展开更多
As the chemical industry grapples with the need for more eco-friendly practices,the use of water as a reaction medium is gaining attraction in organic transformations.This mini-review delves into Pd-catalyzed reaction...As the chemical industry grapples with the need for more eco-friendly practices,the use of water as a reaction medium is gaining attraction in organic transformations.This mini-review delves into Pd-catalyzed reactions that utilize the "on-water" mechanism,spanning from 2019 to late 2023.These reactions are neatly categorized into several types: (A) Catalytic C—H activations,(B) Mizoroki- Heck-type reactions,(C) Suzuki-Miyaura reactions,and (D) Cyclization reactions.By showcasing the potential of water as a sustainable reaction medium for organic transformations,these reactions leave no doubt about the importance of embracing eco-friendly practices in the chemical industry.Key Scientists In 1980,a seminal work by Breslow et al.showed an acceleration of reaction rate in the Diels-Alder reaction.Sharpless and co-workers noted a significant increase in the rate of the [2σ+2σ+2π] cycloaddition of quadricyclane and dimethyl azodicarboxylate (DMAD) when the reaction was conducted in water,as opposed to when it was carried out in organic solvents.The term "on-water" was then coined to describe this phenomenon.This strategy was further expanded to transition-metal catalyzed transformations by Ackermann in 2011.Later,Varma and Leazer disclosed a Pd-catalyzed Mizoroki-Heck type arylation of alkenes with diaryliodonium salts “on-water”.The enantioselective version of "on-water" process was not realized until 2014 by the Zhou group.Later on,the Schaub group described a Pd-catalyzed Suzuki–Miyaura coupling reaction of electron-poor aryl chlorides with water,using only 50 ppm of catalyst loading.Very recently,Liu and Lin extended the "on-water" strategy to Pd-catalyzed double Mizoroki-Heck reactions.This mini-review has focused on Pd-catalyzed reactions involving the “on-water” mechanism.展开更多
Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical significance.According to statist...Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical significance.According to statistics,over 80%of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods.In recent years,with the advancement of basic research and new technologies,the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets.Among them,targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets.This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells.This new form of drug development includes various types such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting Chimaera(LYTAC),autophagosometethering compound(ATTEC),autophagy-targeting chimera(AUTAC),autophagy-targeting chimera(AUTOTAC),degrader-antibody conjugate(DAC).This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets.Finally,the article looks forward to the future development direction and application prospects of targeted protein degradation technology.展开更多
Paraquat(PQ)has been used as an herbicide worldwide because of its potent activity against weeds.However,it is highly toxic to humans.The very high fatality of PQ poisoning is due to its inherent toxicity and the lack...Paraquat(PQ)has been used as an herbicide worldwide because of its potent activity against weeds.However,it is highly toxic to humans.The very high fatality of PQ poisoning is due to its inherent toxicity and the lack of any effective treatment.Consequently,developing a non-toxic herbicide with comparable efficacy to PQ will contribute to global food security and help prevent PQ-related fatalities.Herein,we report a new herbicide called dienediamine,which was discovered from how to intervene the redox cycle of PQ,an inherent toxicity nature.Dienediamine,the“reduced"form of PQ with no function as an electron transfer agent,was shown to be non-toxic through comprehensive in vivo and in vitro experiments at molar concentrations equivalent to PQ's absolute lethal dose.Remarkably,dienediamine can undergo conversion to PQ under natural sunlight and ambient air conditions,exhibiting herbicidal activities that are comparable to those of PQ.The conversion of dienediamine to PQ,which is toxic to chloroplasts,is the key mechanism underlying its potent herbicidal activity.Our study discovers that dienediamine is a safe and superior alternative to PQ,possessing significant potential for application in sustainable agriculture globally.展开更多
To the Editor:The papain-like protease(PL^(pro)),as one of the most important proteases of SARS-CoV-2,has emerged as a highly promising target protein,its inhibitor probably holds dual potentials,namely blocking the c...To the Editor:The papain-like protease(PL^(pro)),as one of the most important proteases of SARS-CoV-2,has emerged as a highly promising target protein,its inhibitor probably holds dual potentials,namely blocking the cleavage of viral polyprotein and intercepting the deubiquitination and deISGylation functions to restore antiviral immunity1.展开更多
Accurate researches on the surface plasmon resonance(SPR)-based applications of chiral plasmonic metal nanoparticles(NPs)still remain a great challenge.Herein,a series of chiral plasmonic metal NPs,e.g.,chiral Au nano...Accurate researches on the surface plasmon resonance(SPR)-based applications of chiral plasmonic metal nanoparticles(NPs)still remain a great challenge.Herein,a series of chiral plasmonic metal NPs,e.g.,chiral Au nanorods(c-Au NRs),c-Au@Ag core–shell,and c-Au@TiO_(2) core–shell NRs,with different chiroptical activities have been produced.Plasmonic circular dichroism(PCD)bands of c-Au NRs can be precisely tailored by tuning the longitudinal SPR(LSPR)and amount of Au NRs as seeds.Besides,a shift of PCD bands within ultraviolet–visible–near infrared ray(UV–vis–NIR)region can also be achieved through the functionalization of a shell of another metal or semiconductor.Interestingly,chirality transfer from c-Au core to Ag shell leads to new PCD bands at the near-UV region.The tuning of PCD bands and chirality transfer are confirmed by our developed theoretical model.Developing chiral Au NRs-based chiral plasmonic nanomaterials with tunable chiroptical activities will be helpful to understand the structure-direct PCD and to extend circularly polarized-based applications.展开更多
Citation of this article:Gu CY,Lee TKW.CircTUBD1:A Nov-el Circular RNA Molecule as a Therapeutic Target in Radiation-induced Liver Fibrosis.J Clin Transl Hepatol 2022;10(4):571-573.doi:10.14218/JCTH.2022.00132.Primary...Citation of this article:Gu CY,Lee TKW.CircTUBD1:A Nov-el Circular RNA Molecule as a Therapeutic Target in Radiation-induced Liver Fibrosis.J Clin Transl Hepatol 2022;10(4):571-573.doi:10.14218/JCTH.2022.00132.Primary liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer mortality worldwide.1 Liver transplantation and surgical resection are two curative therapeutic options for liver cancer patients at the early stages.However,most patients are diagnosed at advanced stages.展开更多
Comprehensive Summary The conversion of CF3-alkenes to gem-difluoroalkenes using reductive cross-coupling strategy has received much attention in recent years,however,the use of green and readily available reducing sa...Comprehensive Summary The conversion of CF3-alkenes to gem-difluoroalkenes using reductive cross-coupling strategy has received much attention in recent years,however,the use of green and readily available reducing salt to mediate these reactions remains to be explored.In this work,a concise construction of gem-difluoroalkenes,which requires neither a catalyst nor a metal reducing agent,was established.Rongalite,a safe and inexpensive industrial product,was employed as both a radical initiator and reductant.This procedure was compatible with both linear and cyclic diaryliodonium salts,enabling a wide variety of substrates(>70 examples).The utility of this approach was demonstrated through gram-scale synthesis and efficient late-stage functionalizations of anti-inflammatory drugs.展开更多
基金We are very grateful for the financial support from the National Natural Science Foundation of China(Grant Nos.:82170406,81970238,and 32111530119)Shanghai Municipal Science and Technology Major Project,China(Grant No.:2018SHZDZX01)+1 种基金The Royal Society UK(Grant No.:IEC\NSFC\201094)the Commonwealth Scholarship Commission UK(Grant No.:NGCA-2020-43).
文摘The solute carrier family 12(SLC12)of cation-chloride cotransporters(CCCs)comprises potassium chloride cotransporters(KCCs,e.g.KCC1,KCC2,KCC3,and KCC4)-mediated Cl^(-)extrusion,and sodium potassium chloride cotransporters(N[K]CCs,NKCC1,NKCC2,and NCC)-mediated Cl^(-)loading.The CCCs play vital roles in cell volume regulation and ion homeostasis.Gain-of-function or loss-of-function of these ion transporters can cause diseases in many tissues.In recent years,there have been considerable advances in our understanding of CCCs'control mechanisms in cell volume regulations,with many techniques developed in studying the functions and activities of CCCs.Classic approaches to directly measure CCC activity involve assays that measure the transport of potassium substitutes through the CCCs.These techniques include the ammonium pulse technique,radioactive or nonradioactive rubidium ion uptakeassay,and thallium ion-uptake assay.CCCs'activity can also be indirectly observed by measuring gaminobutyric acid(GABA)activity with patch-clamp electrophysiology and intracellular chloride concentration with sensitive microelectrodes,radiotracer^(36)Cl^(-),and fluorescent dyes.Other techniques include directly looking at kinase regulatory sites phosphorylation,flame photometry,22Nat uptake assay,structural biology,molecular modeling,and high-throughput drug screening.This review summarizes the role of CCCs in genetic disorders and cell volume regulation,current methods applied in studying CCCs biology,and compounds developed that directly or indirectly target the CCCs for disease treatments.
基金supported in part by grants from the National Key Research and Development Program of China(2022YFC2303100)the National Natural Science Foundation of China(22207117).
文摘Cell-free expression systems have emerged as a versatile and powerful platform for metabolic engineering,biosynthesis and synthetic biology studies.Nevertheless,successful examples of the synthesis of complex natural products using this system are still limited.Bicyclomycin,a structurally unique and complex diketopiperazine alkaloid,is a clinically promising antibiotic that selectively inhibits the transcription termination factor Rho.Here,we established a modular cell-free expression system with cascade catalysis for the biosynthesis of bicyclomycin from a chemically synthesized cyclodipeptide.The six cell-free expressed biosynthetic enzymes,including five iron-andα-ketoglutarate-dependent dioxygenases and one cytochrome P450 monooxygenase,were active in converting their substrates to the corresponding products.The co-expressed enzymes in the cell-free module were able to complete the related partial pathway.In vitro biosynthesis of bicyclomycin was also achieved by reconstituting the entire biosynthetic pathways(i.e.,six enzymes)using the modular cell-free expression system.This study demonstrates that the modular cell-free expression system can be used as a robust and promising platformforthe biosynthesis of complex antibiotics.
基金supported by the National Natural Science Foundation of China 82273961(Ming-Wei Wang),82073904(MingWei Wang),81872915(Ming-Wei Wang),82273985(Dehua Yang)and 81973373(Dehua Yang)Shanghai Municipality Science and Technology Development Fund 21JC1401600(Dehua Yang)and 23XD1400900(Dehua Yang)+3 种基金National Science&Technology Major Project of China-Key New Drug Creation and Manufacturing Program 2018ZX09735-001(Ming-Wei Wang)and 2018ZX097110002-002-005(Dehua Yang)STI2030-Major Project 2021ZD0203400(Qingtong Zhou)the National Key Basic Research Program of China 2018YFA0507000(Ming-Wei Wang)Hainan Provincial Major Science and Technology Project ZDKJ2021028(Dehua Yang and Qingtong Zhou)。
文摘To the Editor:G protein-coupled receptors(GPCRs)are the largest group of membrane proteins with over 800 members,characteristic of a seven transmembrane domain1.By playing crucial roles in regulation of various physiological processes,GPCRs have been implicated in many diseases including diabetes,obesity,depression and cancer.To initiate different intracellular responses,GPCRs mainly interact with three families of effector proteins upon agonist binding:the heterotrimeric G proteins,G protein-coupled receptor kinases(GRKs)and arrestins1.
基金the National Natural Science Foundation of China(22271194 and 22371295)the Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture(Grant No.XTD 2210)the Science and Technology Commission of Shanghai Municipality(20XD1404700)is greatly appreciated.
文摘Comprehensive Summary,Valbenazine(Ingrezza),a potent and highly selective inhibitor of vesicular monoamine transporter type 2(VMAT2)through the active metabolite hydrotetrabenazine(HTBZ),has been approved for the treatment of tardive dyskinesia and,very recently,for chorea,which is associated with Huntington's disease.Despite numerous synthetic efforts dedicated to the synthesis of HTBZ,the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction.Herein,we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3-dipolar cycloaddition and enzymatic kinetic resolution.The cascade process includes cycloaddition,N—O bond cleavage,and lactamization,which proved to be operationally simple.The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline(THIQ)-fused piperidine in the production of medically significant compounds,such as yohimbine and reserpine.
基金We thank Prof.Junying Yuan(IRCBC of CAS,Shanghai,China)and Dr.Jidong Zhu(Etern Therapeutics,Shanghai,China)for their generous help on this work,Dr.Sudan He(ISM of CAMS,Suzhou,China)for providing RIPK3-FKBP NIH/3T3 cells,and National Facility for Protein Science in Shanghai(China)for the help in animal studies.This work was supported by grants from the National Natural Science Foundation of China(Grants Nos.21837004,82151212,and 32170755)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39050500,China)Shanghai Municipal Science and Technology Major Project(Grant No.2019SHZDZX02,China).
文摘Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical evaluation.Recently,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge.Here,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i.We also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases.Collectively,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.
基金supported in part by grants from the National Key Research and Development Program of China(2018YFA0901900)the National Natural Science Foundation of China(22137009)the China Postdoctoral Science Foundation(2020M671271).
文摘A 61-kb biosynthetic gene cluster(BGC),which is accountable for the biosynthesis of hibarimicin(HBM)B from Microbispora rosea subsp.hibaria TP-A0121,was heterologously expressed in Streptomyces coelicolor M1154,which generated a trace of the target products but accumulated a large amount of shunt products.Based on rational analysis of the relevant secondary metabolism,directed engineering of the biosynthetic pathways resulted in the high production of HBM B,as well as new HBM derivates with improved antitumor activity.These results not only establish a biosynthetic system to effectively synthesize HBMs-a class of the largest and most complex Type-Ⅱpolyketides,with a unique pseudo-dimeric structure-but also set the stage for further engineering and deep investigation of this complex biosynthetic pathway toward potent anticancer drugs.
基金the Research Grants Council of the Hong Kong Special Administrative Region,China(PolyU 15302821,15300220,and 25301819)the National Natural Science Foundation of China(21972122)for their financial support.
文摘Comprehensive Summary This paper presents the first general examples of palladium-catalyzed desulfinative cross-coupling reaction of polyhalogenated aryl triflates with aryl sulfinate salts showing an inversion of the conventional reactivity order of C-Br>C-Cl>C-OTf.The catalyst system,comprising of Pd(OAc)_(2)and tBuPhSelectPhos,exhibited excellent catalytic reactivity and chemoselectivity toward this reaction.This reaction had a wide range of substrate scopes and provided a simple and efficient method for the construction of functionalized biaryl motifs.Notably,the C-H···Pd interaction from the methine hydrogen of the C2-cyclohexyl group of the indolyl phosphine ligand with the Pd center may contribute a key factor in reactivity and chemoselectivity.Assisting with density functional theory(DFT)calculations,the results revealed that the oxidative addition step in this reaction was a controlling-chemoselectivity step.
基金supported by the National Natural Science Foundation of China(22337005,22277133,91753126)the Youth Innovation Promotion Association(CAS 2023266)+1 种基金the CAS Interdisciplinary Innovation Team(JCTD-2020-16)the Program of Shanghai Academic/Technology Research Leader(21XD1424700).
文摘The control of protein functions with light is valuable for spatiotemporal probing of biological systems.Current small-molecule photo-modulation methods include the light-induced uncaging of inhibitors and chromophore-assisted light inactivation with reactive oxygen species(ROS).However,the constant target protein expression results in inadequate photo-modulation efficiency,particularly for less potent inhibitors and chromophores.Herein,we report a novel bifunctional small-molecule ligands strategy to photo-modulate gene-editing enzymes CRISPR/Cas9.A coumarin-derived small-molecule ligand Bhc-BRD0539 is developed to uncage the active inhibitor upon light irradiation and to generate ROS in the Cas9 proximity for the dual inhibition of Cas9 activity.Our results highlight the synergistic photo-modulation with bifunctional small-molecule ligands,which offers a valuable addition to current CRISPR/Cas9 photo-modulation technologies and may extend to other protein classes.
基金supported by the National Key Research and Development Program of China(2023YFD1800100 to Feng X and Bai Y)the National Natural Science Foundation of China(22177031 to Feng X,92163127 to Bai Y,82102415 to Wan M,and 82304277 to Zhang C)+4 种基金the Natural Science Foundation of Hunan Province(2024JJ4007 and 2024RC3078 to Feng X,2022RC1107 and 2024JJ2010 to Bai Y)the Natural Science Foundation of Changsha(kq2208050 to Zhang C)the Health and Medical Research Fund(HMRF),Hong Kong SAR(22210412to Wong WL)the Independent Research Project of the College of Advanced Interdisciplinary Studies of NUDT(22-ZZKY-03 to Pu H)the Project of Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs(2023TP1013)。
文摘The global antibiotic resistance crisis necessitates urgent solutions.One innovative approach involves potentiating antibiotics and non-antibiotic drugs with adjuvants or boosters.A major drawback of these membrane-active boosters is their limited biocompatibility,as they struggle to differentiate between prokaryotic and eukaryotic membranes.This study reports the chemical biology investigation of a dual-action oligoamidine(OA1)booster with a glutathione-triggered decomposition mechanism.OA1,when combined with other antimicrobial molecules,exhibits a triple-targeting mechanism including cell membrane disruption,DNA targeting,and intracellular enzyme inhibition.This multi-targeting mechanism not only enhances the in vitro and in vivo eradication of antibiotic-resistant“ESKAPE”pathogens,but also suppresses the development of bacterial resistance.Furthermore,OA1 maintains its activity in bacterial cells by creating an oxidative environment,while it quickly decomposes in mammalian cells due to high glutathione levels.These mechanistic insights and design principles may provide a feasible approach to develop novel antimicrobial agents and effective anti-resistance combination therapies.
基金support from the National Natural Science Foundation of China(22101296)the State Key Laboratory of Systems Medicine for Cancer(SB23-09,KF2130-93).
文摘As the chemical industry grapples with the need for more eco-friendly practices,the use of water as a reaction medium is gaining attraction in organic transformations.This mini-review delves into Pd-catalyzed reactions that utilize the "on-water" mechanism,spanning from 2019 to late 2023.These reactions are neatly categorized into several types: (A) Catalytic C—H activations,(B) Mizoroki- Heck-type reactions,(C) Suzuki-Miyaura reactions,and (D) Cyclization reactions.By showcasing the potential of water as a sustainable reaction medium for organic transformations,these reactions leave no doubt about the importance of embracing eco-friendly practices in the chemical industry.Key Scientists In 1980,a seminal work by Breslow et al.showed an acceleration of reaction rate in the Diels-Alder reaction.Sharpless and co-workers noted a significant increase in the rate of the [2σ+2σ+2π] cycloaddition of quadricyclane and dimethyl azodicarboxylate (DMAD) when the reaction was conducted in water,as opposed to when it was carried out in organic solvents.The term "on-water" was then coined to describe this phenomenon.This strategy was further expanded to transition-metal catalyzed transformations by Ackermann in 2011.Later,Varma and Leazer disclosed a Pd-catalyzed Mizoroki-Heck type arylation of alkenes with diaryliodonium salts “on-water”.The enantioselective version of "on-water" process was not realized until 2014 by the Zhou group.Later on,the Schaub group described a Pd-catalyzed Suzuki–Miyaura coupling reaction of electron-poor aryl chlorides with water,using only 50 ppm of catalyst loading.Very recently,Liu and Lin extended the "on-water" strategy to Pd-catalyzed double Mizoroki-Heck reactions.This mini-review has focused on Pd-catalyzed reactions involving the “on-water” mechanism.
基金supported by the National Key R&D Program of China(2021YFA1300200,2021YFA1302100 and 2020YFE0202200)the National Natural Science Foundation of China(82125034,82330115)。
文摘Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical significance.According to statistics,over 80%of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods.In recent years,with the advancement of basic research and new technologies,the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets.Among them,targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets.This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells.This new form of drug development includes various types such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting Chimaera(LYTAC),autophagosometethering compound(ATTEC),autophagy-targeting chimera(AUTAC),autophagy-targeting chimera(AUTOTAC),degrader-antibody conjugate(DAC).This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets.Finally,the article looks forward to the future development direction and application prospects of targeted protein degradation technology.
基金the National Nature Science Foundation of China(81971822,81270136,82188101,21725205)National Key R&D Program of China(2021YFF0701601,2022YFA1503702).
文摘Paraquat(PQ)has been used as an herbicide worldwide because of its potent activity against weeds.However,it is highly toxic to humans.The very high fatality of PQ poisoning is due to its inherent toxicity and the lack of any effective treatment.Consequently,developing a non-toxic herbicide with comparable efficacy to PQ will contribute to global food security and help prevent PQ-related fatalities.Herein,we report a new herbicide called dienediamine,which was discovered from how to intervene the redox cycle of PQ,an inherent toxicity nature.Dienediamine,the“reduced"form of PQ with no function as an electron transfer agent,was shown to be non-toxic through comprehensive in vivo and in vitro experiments at molar concentrations equivalent to PQ's absolute lethal dose.Remarkably,dienediamine can undergo conversion to PQ under natural sunlight and ambient air conditions,exhibiting herbicidal activities that are comparable to those of PQ.The conversion of dienediamine to PQ,which is toxic to chloroplasts,is the key mechanism underlying its potent herbicidal activity.Our study discovers that dienediamine is a safe and superior alternative to PQ,possessing significant potential for application in sustainable agriculture globally.
基金National Natural Science Foundation of China(82151219,82130105)the Strategic Priority Research Program of Chinese Academy of Sciences(SIMM010109,SIMM010111)Shanghai Institute of Materia Medica of Chinese Academy of Sciences(SIMM0120231003)for the financial support.
文摘To the Editor:The papain-like protease(PL^(pro)),as one of the most important proteases of SARS-CoV-2,has emerged as a highly promising target protein,its inhibitor probably holds dual potentials,namely blocking the cleavage of viral polyprotein and intercepting the deubiquitination and deISGylation functions to restore antiviral immunity1.
基金supported by the National Natural Science Foundation of China(Nos.21902148,11774036,12174032,and 22071172)the National Key Research and Development Program of China(No.2017YFA0303400)+1 种基金the National Natural Science Foundation of China-Research Grant Council(No.11861161002)K.Y.W.acknowledges the support by the Patrick S.C.Poon endowed professorship.
文摘Accurate researches on the surface plasmon resonance(SPR)-based applications of chiral plasmonic metal nanoparticles(NPs)still remain a great challenge.Herein,a series of chiral plasmonic metal NPs,e.g.,chiral Au nanorods(c-Au NRs),c-Au@Ag core–shell,and c-Au@TiO_(2) core–shell NRs,with different chiroptical activities have been produced.Plasmonic circular dichroism(PCD)bands of c-Au NRs can be precisely tailored by tuning the longitudinal SPR(LSPR)and amount of Au NRs as seeds.Besides,a shift of PCD bands within ultraviolet–visible–near infrared ray(UV–vis–NIR)region can also be achieved through the functionalization of a shell of another metal or semiconductor.Interestingly,chirality transfer from c-Au core to Ag shell leads to new PCD bands at the near-UV region.The tuning of PCD bands and chirality transfer are confirmed by our developed theoretical model.Developing chiral Au NRs-based chiral plasmonic nanomaterials with tunable chiroptical activities will be helpful to understand the structure-direct PCD and to extend circularly polarized-based applications.
基金This study was supported by the RGC General Research Fund(15102020 to T.K.Lee)Collaborative Research Fund(C7026-18G)Research Impact Fund(R5050-18F&R7022-20).
文摘Citation of this article:Gu CY,Lee TKW.CircTUBD1:A Nov-el Circular RNA Molecule as a Therapeutic Target in Radiation-induced Liver Fibrosis.J Clin Transl Hepatol 2022;10(4):571-573.doi:10.14218/JCTH.2022.00132.Primary liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer mortality worldwide.1 Liver transplantation and surgical resection are two curative therapeutic options for liver cancer patients at the early stages.However,most patients are diagnosed at advanced stages.
基金supported by the National Natural Science Foundation of China(Grants 21971080,21971079,21772051)This work was also supported by the 111 Project B17019.
文摘Comprehensive Summary The conversion of CF3-alkenes to gem-difluoroalkenes using reductive cross-coupling strategy has received much attention in recent years,however,the use of green and readily available reducing salt to mediate these reactions remains to be explored.In this work,a concise construction of gem-difluoroalkenes,which requires neither a catalyst nor a metal reducing agent,was established.Rongalite,a safe and inexpensive industrial product,was employed as both a radical initiator and reductant.This procedure was compatible with both linear and cyclic diaryliodonium salts,enabling a wide variety of substrates(>70 examples).The utility of this approach was demonstrated through gram-scale synthesis and efficient late-stage functionalizations of anti-inflammatory drugs.