Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing p...Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity,from weak hits to highly potent drugs.Here,we summarize NMR applications in fragment-based hit-to-lead evolution,including the construction of a fragment library,screening methods,spectra processing,and the delineation of the protein-ligand binding modes.These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years,and they are expected to continue to provide new insights in the future.展开更多
Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structur...Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structure prediction and protein design(Madani et al., 2023). However, there is massive biomedical knowledge not curated in the form of structured data but hidden in primary scientific literature.展开更多
During the ongoing pandemic,providing treatment consisting of effective,low-cost oral antiviral drugs at an early stage of SARSCoV-2 infection has been a priority for controling COVID-19.Although Paxlovid and molnupir...During the ongoing pandemic,providing treatment consisting of effective,low-cost oral antiviral drugs at an early stage of SARSCoV-2 infection has been a priority for controling COVID-19.Although Paxlovid and molnupiravir have received emergency approval from the FDA,some side effect concerns have emerged,and the possible oral agents are stillimited,resulting in optimized drug development becoming an urgent requirement.展开更多
The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million s...The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.展开更多
Dear Editor,Recent achievements in large-scale pre-trained models like GPT-3 and PanGu-α have demonstrated astounding performances in many downstream tasks of natural language processing (NLP),confirming AI to be use...Dear Editor,Recent achievements in large-scale pre-trained models like GPT-3 and PanGu-α have demonstrated astounding performances in many downstream tasks of natural language processing (NLP),confirming AI to be user-oriented for even industrial applications.Deep learning has been recognized as the most promising technology for pharmaceuticals,a powerful molecule pre-trained model that could economize researchers’tons of time.For the strategic application of AI capabilities to the drug discovery field,we pre-trained a model called PanGu Drug Model with 1.7 billion small molecules from ZINC20 (Irwin et al.,2020),DrugSpaceX(Yang et al.,2021),and UniChem (Chambers et al.,2013).展开更多
Monitoring the physiological changes of organelles is essential for understanding the local biological information of cells and for improving the diagnosis and therapy of diseases.Currently,fluorescent probes are cons...Monitoring the physiological changes of organelles is essential for understanding the local biological information of cells and for improving the diagnosis and therapy of diseases.Currently,fluorescent probes are considered as the most powerful tools for imaging and have been widely applied in biomedical fields.However,the expected targeting effects of these probes are often inconsistent with the real experiments.The design of fluorescent probes mainly depends on the empirical knowledge of researchers,which was inhibited by limited chemical space and low efficiency.Herein,we proposed a novel multilevel framework for the prediction of organelle-targeted fluorescent probes by employing advanced artificial intelligence algorithms.In this way,not only the targeting mechanism could be interpreted beyond intuitions but also a quick evaluation method could be established for the rational design.Furthermore,the targeting and imaging powers of the optimized and synthesized probes based on this methodology were verified by quantitative calculation and experiments.展开更多
Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure wit...Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).展开更多
Natural products(NPs), including traditional Chinese medicine(TCM), have been long and widely used in the prevention and treatment of central nervous system(CNS) diseases by virtue of their abundant sources, diverse s...Natural products(NPs), including traditional Chinese medicine(TCM), have been long and widely used in the prevention and treatment of central nervous system(CNS) diseases by virtue of their abundant sources, diverse structures, and novel activities.In this review article, we intend to summarize and discuss the situation or status of the clinical employments or trials of the NPs and their derivatives with CNS activities. NPs that have been extensively studied in preclinical research in recent years are also included. The compounds presented in this review are classified according to their indications and followed by details such as natural sources, possible biological mechanisms, and development status, while a considerable proportion of them are found in TCM. In addition, some drug combinations with synergistic effects are also mentioned. According to their impressive therapeutic effects and novel chemical structures, NPs are not only effective therapeutic remedies in clinic, but also lead compounds for structural modification, which indicate that nature brings new avenues to the therapy of CNS diseases.展开更多
Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology,the computer-aided drug design techniques have been successfully applied in almost every stage...Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology,the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical trials.Owing to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence(AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening,activity scoring, quantitative structure-activity relationship(QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity(ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability,deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules,which will further promote the application of AI technologies in the field of drug design.展开更多
Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein...Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol(LDL-C).A novel series of tetrahydroprotoberberine derivatives(THPBs)were designed,synthesized,and evaluated as PCSK9 modulators for the treatment of hyperlipidemia.Among them,eight compounds exhibited excellent activities in downregulatinghepatic PCSK9 expression better than berberine in HepG2 cells.In addition,five compounds 15,18,22,(R)-22,and(S)-22 showed better performance in the low-density lipoprotein,labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethyl-indocarbocyanine perchlorate(Dil-LDL)uptake assay,compared with berberine at the same concentration.Compound 22,selected for in vivo evaluation,demonstrated significant reductions of total cholesterol(TC)and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile.Further exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells.Additional results of human ether-ago-go related gene(hERG)inhibition assay indicated the potential druggability for compound 22,which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.展开更多
We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by...We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by three doses(56 in low dose,61 in middle dose,and 59 in high dose)in addition to standard care.The control group was composed of 59 patients who received standard therapy alone.Treatment with SHL was not associated with a difference from standard care in the time to disease recovery.Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group(93.4%vs.73.9%,P=0.006).Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia,which was evaluated by density reduction of inflammatory focus from baseline,at day 7(mean difference(95%CI),−46.39(−86.83 to−5.94)HU;P=0.025)and day 14(mean difference(95%CI),−74.21(−133.35 to−15.08)HU;P=0.014).No serious adverse events occurred in the SHL groups.This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.展开更多
Coronavirus disease 2019(COVID-19)is a pandemic with no specific drugs and high fatality.The most urgent need is to find effective treatments.We sought to determine whether hydroxychloroquine(HCQ)application may reduc...Coronavirus disease 2019(COVID-19)is a pandemic with no specific drugs and high fatality.The most urgent need is to find effective treatments.We sought to determine whether hydroxychloroquine(HCQ)application may reduce the death risk of critically ill COVID-19 patients.In this retrospective study,we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital,Wuhan,from February 1,2020 to April 4,2020.All 550 patients received comparable basic treatments including antiviral drugs and antibiotics,and 48 of them were treated with oral HCQ treatment(200 mg twice a day for 7–10 days)in addition to the basic treatments.Primary endpoint is fatality of patients,and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine(NHCQ)treatments.We found that fatalities are 18.8%(9/48)in HCQ group,which is significantly lower than 47.4%(238/502)in the NHCQ group(P<0.001).The time of hospital stay before patient death is 15(10–21)days and 8(4–14)days for the HCQ and NHCQ groups,respectively(P<0.05).The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2(8.3–118.9)pg mL–1 at the beginning of the treatment to 5.2(3.0–23.4)pg mL–1(P<0.05)at the end of the treatment in the HCQ group but there is no change in the NHCQ group.These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm.Therefore,HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients,with possible outcome of saving lives.展开更多
The ongoing pandemic of severe acute respiratory syn・drome coronavirus 2(SARS・CoV・2),referred to as coronavirus disease 2019(COVID-19),has caused over 13 million infections and over 560,000 deaths worldwide(https://ww...The ongoing pandemic of severe acute respiratory syn・drome coronavirus 2(SARS・CoV・2),referred to as coronavirus disease 2019(COVID-19),has caused over 13 million infections and over 560,000 deaths worldwide(https://www.who.int/emergencies/diseases/novel・coron avirus-2019/sit uation-reports),posing a significant threat to globally public health and economics.At present,no efficacious antiviral drugs and vaccines have been approved for the prophylaxis or treatment of COVID-19.Tremendous efforts have been made to develop drug and vaccine against SARS-CoV-2.The main protease(Mpro,also called 3CLpro)is an attractive drug target among coronaviruses,and several potent inhibitors of the SARS-CoV-23CLpro together with their crystal structures in complex with the protease have been reported(Dai et al.,2020;Jin et al.,2020;Zhang et al.,2020).展开更多
A fundamental challenge that arises in biomedicine is the need to characterize compounds in a relevant cellular context in order to reveal potential on-target or offtarget effects.Recently,the fast accumulation of gen...A fundamental challenge that arises in biomedicine is the need to characterize compounds in a relevant cellular context in order to reveal potential on-target or offtarget effects.Recently,the fast accumulation of gene transcriptional profiling data provides us an unprecedented opportunity to explore the protein targets of chemical compounds from the perspective of cell transcriptomics and RNA biology.Here,we propose a novel Siamese spectral-based graph convolutional network(SSGCN)model for inferring the protein targets of chemical compounds from gene transcriptional profiles.Although the gene signature of a compound perturbation only provides indirect clues of the interacting targets,and the biological networks under different experiment conditions further complicate the situation,the SSGCN model was successfully trained to learn from known compound-target pairs by uncovering the hidden correlations between compound perturbation profiles and gene knockdown profiles.On a benchmark set and a large time-split validation dataset,the model achieved higher target inference accuracy as compared to previous methods such as Connectivity Map.Further experimental validations of prediction results highlight the practical usefulness of SSGCN in either inferring the interacting targets of compound,or reversely,in finding novel inhibitors of a given target of interest.展开更多
Biological macromolecules(proteins,nucleic acids,polysaccharides,etc.)are the building blocks of life,which constantly undergo chemical modifications that are often reversible and spatial-temporally regulated.These dy...Biological macromolecules(proteins,nucleic acids,polysaccharides,etc.)are the building blocks of life,which constantly undergo chemical modifications that are often reversible and spatial-temporally regulated.These dynamic properties of chemical modifications play fundamental roles in physiological processes as well as pathological changes of living systems.The Major Research Project(MRP)funded by the National Natural Science Foundation of China(NSFC)—"Dynamic modifications of biomacromolecules:mechanism and chemical interventions"aims to integrate cross-disciplinary approaches at the interface of chemistry,life sciences,medicine,mathematics,material science and information science with the following goals:(i)developing specific labeling techniques and detection methods for dynamic chemical modifications of biomacromolecules,(ii)analyzing the molecular mechanisms and functional relationships of dynamic chemical modifications of biomacromolecules,and(iii)exploring biomacromolecules and small molecule probes as potential drug targets and lead compounds.展开更多
Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen plat...Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATPcompetitive inhibitor of PGK1 with an affinity of Kd= 99.08 nmol/L. DC-PGKI stabilizes PGK1in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition,DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages.Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2(nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium(DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.展开更多
基金These authors contributed equally to this work. Acknowledgments This work was supported by the State Key Program of Basic Research of China grants （2009CB918502 and 2006CB500803）, China Postdoctoral Science Foundation grants （20080440095 and 20060400184）, and the National Natural Science Foundation of China grants （20721003, 20720102040, 30830035 and 30621062）.
基金We thank the Ministry of Science and Technology of China(2019YFA0508400 and 2016YFA0500700)the National Natural Science Foundation of China(21874123 and 21807095)Collaborative Innovation Program of Hefei Science Center,CAS(2020HSC-CIP009)for the financial support.
文摘Considerable developments have been observed in fragment-based lead/drug discovery(FBLD/FBDD)recently,with four drugs approved and many others under investigation.Nuclear magnetic resonance(NMR)has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity,from weak hits to highly potent drugs.Here,we summarize NMR applications in fragment-based hit-to-lead evolution,including the construction of a fragment library,screening methods,spectra processing,and the delineation of the protein-ligand binding modes.These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years,and they are expected to continue to provide new insights in the future.
基金supported by the National Natural Science Foundation of China(T2225002,82273855)Lingang Laboratory(LG202102-01-02)the National Key Research and Development Program of China(2022YFC3400504)。
文摘Dear Editor,Great progress has been made using artificial intelligence(AI) techniques in learning knowledge from biomedical databases in recent years, revolutionizing the study of many fields, such as protein structure prediction and protein design(Madani et al., 2023). However, there is massive biomedical knowledge not curated in the form of structured data but hidden in primary scientific literature.
基金This work was supported by grants from the National Natural Science Foundation of China(U22A20379,31970165)the National Key Research and Development Plan of China(2021YFC2300700,2022YFC2303300)+1 种基金the Special Foundation of the Chinese Academy of Sciences(2022000025)Shanghai Science and Technology Committee in China(Number:21S11903100).
文摘During the ongoing pandemic,providing treatment consisting of effective,low-cost oral antiviral drugs at an early stage of SARSCoV-2 infection has been a priority for controling COVID-19.Although Paxlovid and molnupiravir have received emergency approval from the FDA,some side effect concerns have emerged,and the possible oral agents are stillimited,resulting in optimized drug development becoming an urgent requirement.
基金supported by the National Key R&D Program of China 2018YFA0507000(B.W,Q.Z.),2018ZX09735001(Y.J.)and 2020YFC0844500(J.L.),the National Science Foundation of China grants 31825010(B.W.),81525024(Q.Z.),81673489(J.L),the Key Research Program of Frontier Sciences,CAS grants QYZDB-SSWSMC024(B.W.)and QYZDB-SSW-SMC054(Q.Z.),Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.),Chinese Academy of Engineering and Jack Ma Foundation 2020-CMKYGG-05(J.D.),the Shanghai Science and Technology Development Funds 20431900200(J.L.)and K.C.Wong Education Foundation(J.L.),Fund of Youth Innovation Promotion Association 2018319(X.C.),and the Hubei Science and Technology Project 2020FCA003(G.X.).Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.)。
文摘The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
文摘Dear Editor,Recent achievements in large-scale pre-trained models like GPT-3 and PanGu-α have demonstrated astounding performances in many downstream tasks of natural language processing (NLP),confirming AI to be user-oriented for even industrial applications.Deep learning has been recognized as the most promising technology for pharmaceuticals,a powerful molecule pre-trained model that could economize researchers’tons of time.For the strategic application of AI capabilities to the drug discovery field,we pre-trained a model called PanGu Drug Model with 1.7 billion small molecules from ZINC20 (Irwin et al.,2020),DrugSpaceX(Yang et al.,2021),and UniChem (Chambers et al.,2013).
基金the National Natural Science Foundation of China(Grant Nos.22003078,82272067,and M-0696)d the Central South University Innovation-Driven Research Program(Grant Nos.2023CXQD004 and 2023QYJC021).
文摘Monitoring the physiological changes of organelles is essential for understanding the local biological information of cells and for improving the diagnosis and therapy of diseases.Currently,fluorescent probes are considered as the most powerful tools for imaging and have been widely applied in biomedical fields.However,the expected targeting effects of these probes are often inconsistent with the real experiments.The design of fluorescent probes mainly depends on the empirical knowledge of researchers,which was inhibited by limited chemical space and low efficiency.Herein,we proposed a novel multilevel framework for the prediction of organelle-targeted fluorescent probes by employing advanced artificial intelligence algorithms.In this way,not only the targeting mechanism could be interpreted beyond intuitions but also a quick evaluation method could be established for the rational design.Furthermore,the targeting and imaging powers of the optimized and synthesized probes based on this methodology were verified by quantitative calculation and experiments.
基金supported by grants from the National Natural Science Foundation of China(81790624[to D.W.W.],81900342[to L.P.]and 81790621[to Y.Z.]).
文摘Epoxyeicosatrienoic acids(EETs)have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase(sEH).Heart failure with preserved ejection fraction(HFpEF)has shown an increased prevalence and worse prognosis over the decades.However,the role of sEH activ-ity in HFpEF remains unclear.We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016.Eight types of sEH-related eicosanoids were measured according to target metabolomics,and their correlation with clinical endpoints was also analyzed.The primary endpoint was cardiac mortality,and the secondary endpoint was a composite of cardiac events,including heart failure(HF)readmission,cardiogenic hospitalization,and all-cause mortal-ity.Furthermore,the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro.Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls.More importantly,sEH activity was positively correlated with cardiac mortality in patients with HFpEF,especially in older patients with arrhythmia.A consistent result was obtained in the multiple adjusted models.Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model.This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function.Clinical trial identifier:NCT03461107(https://clini caltr ials.gov).
基金supported by Special Foundation of Chinese Academy of Sciences for strategic pilot technology (XDA12040105)National Science Foundation for Young Scientists of China (81703338)
文摘Natural products(NPs), including traditional Chinese medicine(TCM), have been long and widely used in the prevention and treatment of central nervous system(CNS) diseases by virtue of their abundant sources, diverse structures, and novel activities.In this review article, we intend to summarize and discuss the situation or status of the clinical employments or trials of the NPs and their derivatives with CNS activities. NPs that have been extensively studied in preclinical research in recent years are also included. The compounds presented in this review are classified according to their indications and followed by details such as natural sources, possible biological mechanisms, and development status, while a considerable proportion of them are found in TCM. In addition, some drug combinations with synergistic effects are also mentioned. According to their impressive therapeutic effects and novel chemical structures, NPs are not only effective therapeutic remedies in clinic, but also lead compounds for structural modification, which indicate that nature brings new avenues to the therapy of CNS diseases.
基金supported by the National Natural Science Foundation of China (21210003 and 81230076 to H.J., 81773634 to M.Z. and 81430084 to K.C.)the “Personalized Medicines-Molecular Signature-based Drug Discovery and Development”, Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12050201 to M.Z.)+1 种基金National Key Research & Development Plan (2016YFC1201003 to M.Z.)the National Basic Research Program (2015CB910304 to X.L.)
文摘Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology,the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical trials.Owing to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence(AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening,activity scoring, quantitative structure-activity relationship(QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity(ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability,deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules,which will further promote the application of AI technologies in the field of drug design.
基金the funds from National Program on Key Basic Research Project of China(2015CB910304)the National Natural Science Foundation(81620108027,21632008,and 21402226,China)+1 种基金National Science&Technology Major Project Key New Drug Creation and Manufacturing Program(2018ZX09711002-012-007,China)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040213)for financial support.
文摘Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol(LDL-C).A novel series of tetrahydroprotoberberine derivatives(THPBs)were designed,synthesized,and evaluated as PCSK9 modulators for the treatment of hyperlipidemia.Among them,eight compounds exhibited excellent activities in downregulatinghepatic PCSK9 expression better than berberine in HepG2 cells.In addition,five compounds 15,18,22,(R)-22,and(S)-22 showed better performance in the low-density lipoprotein,labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethyl-indocarbocyanine perchlorate(Dil-LDL)uptake assay,compared with berberine at the same concentration.Compound 22,selected for in vivo evaluation,demonstrated significant reductions of total cholesterol(TC)and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile.Further exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells.Additional results of human ether-ago-go related gene(hERG)inhibition assay indicated the potential druggability for compound 22,which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.
基金This work was supported by the National Key R&D Program of China(No.2020YFC0841400)Tongji Hospital Clinical Research Project(Nos.XXGZBDYJ009 and 2019YBKY019).
文摘We conducted a randomized,open-label,parallel-controlled,multicenter trial on the use of Shuanghuanglian(SHL),a traditional Chinese patent medicine,in treating cases of COVID-19.A total of 176 patients received SHL by three doses(56 in low dose,61 in middle dose,and 59 in high dose)in addition to standard care.The control group was composed of 59 patients who received standard therapy alone.Treatment with SHL was not associated with a difference from standard care in the time to disease recovery.Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group(93.4%vs.73.9%,P=0.006).Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia,which was evaluated by density reduction of inflammatory focus from baseline,at day 7(mean difference(95%CI),−46.39(−86.83 to−5.94)HU;P=0.025)and day 14(mean difference(95%CI),−74.21(−133.35 to−15.08)HU;P=0.014).No serious adverse events occurred in the SHL groups.This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.
基金Supported in part by projects from Ministry of Science and Technology of China (2020YFC0844500)the National Natural Science Foundation of China (31130031), Emergency Project Fund of Chinese Academy of Sciences (2020YJFK0105)Chinese Academy of Engineering and Ma Yun Foundation (2020-CMKYGG-05).
文摘Coronavirus disease 2019(COVID-19)is a pandemic with no specific drugs and high fatality.The most urgent need is to find effective treatments.We sought to determine whether hydroxychloroquine(HCQ)application may reduce the death risk of critically ill COVID-19 patients.In this retrospective study,we included 550 critically ill COVID-19 patients who need mechanical ventilation in Tongji Hospital,Wuhan,from February 1,2020 to April 4,2020.All 550 patients received comparable basic treatments including antiviral drugs and antibiotics,and 48 of them were treated with oral HCQ treatment(200 mg twice a day for 7–10 days)in addition to the basic treatments.Primary endpoint is fatality of patients,and inflammatory cytokine levels were compared between HCQ and non-hydroxychloroquine(NHCQ)treatments.We found that fatalities are 18.8%(9/48)in HCQ group,which is significantly lower than 47.4%(238/502)in the NHCQ group(P<0.001).The time of hospital stay before patient death is 15(10–21)days and 8(4–14)days for the HCQ and NHCQ groups,respectively(P<0.05).The levels of inflammatory cytokine IL-6 were significantly reduced from 22.2(8.3–118.9)pg mL–1 at the beginning of the treatment to 5.2(3.0–23.4)pg mL–1(P<0.05)at the end of the treatment in the HCQ group but there is no change in the NHCQ group.These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm.Therefore,HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients,with possible outcome of saving lives.
文摘The ongoing pandemic of severe acute respiratory syn・drome coronavirus 2(SARS・CoV・2),referred to as coronavirus disease 2019(COVID-19),has caused over 13 million infections and over 560,000 deaths worldwide(https://www.who.int/emergencies/diseases/novel・coron avirus-2019/sit uation-reports),posing a significant threat to globally public health and economics.At present,no efficacious antiviral drugs and vaccines have been approved for the prophylaxis or treatment of COVID-19.Tremendous efforts have been made to develop drug and vaccine against SARS-CoV-2.The main protease(Mpro,also called 3CLpro)is an attractive drug target among coronaviruses,and several potent inhibitors of the SARS-CoV-23CLpro together with their crystal structures in complex with the protease have been reported(Dai et al.,2020;Jin et al.,2020;Zhang et al.,2020).
文摘A fundamental challenge that arises in biomedicine is the need to characterize compounds in a relevant cellular context in order to reveal potential on-target or offtarget effects.Recently,the fast accumulation of gene transcriptional profiling data provides us an unprecedented opportunity to explore the protein targets of chemical compounds from the perspective of cell transcriptomics and RNA biology.Here,we propose a novel Siamese spectral-based graph convolutional network(SSGCN)model for inferring the protein targets of chemical compounds from gene transcriptional profiles.Although the gene signature of a compound perturbation only provides indirect clues of the interacting targets,and the biological networks under different experiment conditions further complicate the situation,the SSGCN model was successfully trained to learn from known compound-target pairs by uncovering the hidden correlations between compound perturbation profiles and gene knockdown profiles.On a benchmark set and a large time-split validation dataset,the model achieved higher target inference accuracy as compared to previous methods such as Connectivity Map.Further experimental validations of prediction results highlight the practical usefulness of SSGCN in either inferring the interacting targets of compound,or reversely,in finding novel inhibitors of a given target of interest.
文摘Biological macromolecules(proteins,nucleic acids,polysaccharides,etc.)are the building blocks of life,which constantly undergo chemical modifications that are often reversible and spatial-temporally regulated.These dynamic properties of chemical modifications play fundamental roles in physiological processes as well as pathological changes of living systems.The Major Research Project(MRP)funded by the National Natural Science Foundation of China(NSFC)—"Dynamic modifications of biomacromolecules:mechanism and chemical interventions"aims to integrate cross-disciplinary approaches at the interface of chemistry,life sciences,medicine,mathematics,material science and information science with the following goals:(i)developing specific labeling techniques and detection methods for dynamic chemical modifications of biomacromolecules,(ii)analyzing the molecular mechanisms and functional relationships of dynamic chemical modifications of biomacromolecules,and(iii)exploring biomacromolecules and small molecule probes as potential drug targets and lead compounds.
基金the National Key Research and Development Program of China (2021ZD0203900 to Cheng Luo)the National Natural Science Foundation of China (91853205, 81821005 to Cheng Luo)+1 种基金the Science and Technology Commission of Shanghai Municipality (19XD1404700 to Cheng Luo, China)the project of National Multidisciplinary Innovation Team of Traditional Chinese Medicine supported by National Administration of Traditional Chinese Medicine to Cheng Luo, the Lingang Laboratory, Grant No. LG-QS-202206-01.
文摘Glycolytic metabolism enzymes have been implicated in the immunometabolism field through changes in metabolic status. PGK1 is a catalytic enzyme in the glycolytic pathway. Here, we set up a high-throughput screen platform to identify PGK1 inhibitors. DC-PGKI is an ATPcompetitive inhibitor of PGK1 with an affinity of Kd= 99.08 nmol/L. DC-PGKI stabilizes PGK1in vitro and in vivo, and suppresses both glycolytic activity and the kinase function of PGK1. In addition,DC-PGKI unveils that PGK1 regulates production of IL-1β and IL-6 in LPS-stimulated macrophages.Mechanistically, inhibition of PGK1 with DC-PGKI results in NRF2(nuclear factor-erythroid factor 2-related factor 2, NFE2L2) accumulation, then NRF2 translocates to the nucleus and binds to the proximity region of Il-1β and Il-6 genes, and inhibits LPS-induced expression of these genes. DC-PGKI ameliorates colitis in the dextran sulfate sodium(DSS)-induced colitis mouse model. These data support PGK1 as a regulator of macrophages and suggest potential utility of PGK1 inhibitors in the treatment of inflammatory bowel disease.
