238 results on '"Yechun Xu"'
Search Results
52. A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors
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Xiang-lei Zhang, Huan Ge, Leike Zhang, Fang Bai, Bing-qian Li, Yechun Xu, Lili Zhu, Lin Wang, Peng-xuan Ren, Wanchao Yin, Eric H. Xu, Weijuan Shang, Hualiang Jiang, and Honglin Li
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0301 basic medicine ,Drug ,RdRp ,Virus RNA ,viruses ,media_common.quotation_subject ,Emetine ,Microbial Sensitivity Tests ,Antiviral Agents ,Ribosome ,Article ,Virus ,Cell Line ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,SARS-CoV-2 inhibitors ,host ribosome ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Polymerase ,media_common ,Pharmacology ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,SARS-CoV-2 ,Viral translation ,RNA ,General Medicine ,Lycorine ,Virology ,030104 developmental biology ,chemistry ,Drug Design ,030220 oncology & carcinogenesis ,biology.protein ,medicine.drug - Abstract
The COVID-19, caused by SARS-CoV-2, is threatening public health, and there is no effective treatment. In this study, we have implemented a multi-targeted anti-viral drug design strategy to discover highly potent SARS-CoV-2 inhibitors, which simultaneously act on the host ribosome, viral RNA as well as RNA-dependent RNA polymerases, and nucleocapsid protein of the virus, to impair viral translation, frameshifting, replication, and assembly. Driven by this strategy, three alkaloids, including lycorine, emetine, and cephaeline, were discovered to inhibit SARS-CoV-2 with EC50 values of low nanomolar levels potently. The findings in this work demonstrate the feasibility of this multi-targeting drug design strategy and provide a rationale for designing more potent anti-virus drugs.
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- 2021
53. Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2
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Kaixian Chen, Hang Yang, Wenhao Dai, Hong Liu, Hualiang Jiang, Yong Nian, Dirk Jochmans, Rolf Hilgenfeld, Lili Zhu, Hang Xie, Jingjing Peng, Jian Li, Leike Zhang, Yechun Xu, Di Chang, Haixia Su, Jiang Wang, and Johan Neyts
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Male ,Models, Molecular ,Peptidomimetic ,Microbial Sensitivity Tests ,Cysteine Proteinase Inhibitors ,medicine.disease_cause ,Antiviral Agents ,Aldehyde ,Article ,Cell Line ,Mice ,Structure-Activity Relationship ,Pharmacokinetics ,Chlorocebus aethiops ,Drug Discovery ,medicine ,Enterovirus 71 ,Animals ,Humans ,IC50 ,Coronavirus 3C Proteases ,Enterovirus ,EC50 ,chemistry.chemical_classification ,Aldehydes ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,SARS-CoV-2 ,biology.organism_classification ,Acute toxicity ,Biochemistry ,chemistry ,Drug Design ,Molecular Medicine ,Peptidomimetics - Abstract
A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 μM, EC50 = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:65 issue:4 pages:2794-2808 ispartof: location:United States status: published
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- 2021
54. Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate
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Yu Hong, Yu Zhou, Dong Zhang, Hualiang Jiang, Shengtao Xu, H. Eric Xu, Wei Wang, Yechun Xu, Tao Peng, Wanchao Yin, Jian Li, Hai-Yan Zhang, Hong Liu, Dan Zhang, Qiufeng Liu, Qi Gong, Fang Bai, and Yan Fu
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Male ,Drug ,Aché ,media_common.quotation_subject ,Scopolamine ,Pharmacology ,Crystallography, X-Ray ,01 natural sciences ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,Piperidines ,Pharmacokinetics ,Alzheimer Disease ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Donepezil ,Nootropic Agents ,030304 developmental biology ,media_common ,Mice, Inbred ICR ,0303 health sciences ,Molecular Structure ,Acetylcholinesterase ,Effective dose (pharmacology) ,language.human_language ,0104 chemical sciences ,Bioavailability ,Kinetics ,010404 medicinal & biomolecular chemistry ,chemistry ,Drug Design ,Indans ,language ,Molecular Medicine ,Female ,Cholinesterase Inhibitors ,Protein Binding ,medicine.drug - Abstract
The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
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- 2021
55. Discovery, synthesis and mechanism study of 2,3,5-substituted [1,2,4]-thiadiazoles as covalent inhibitors targeting 3C-Like protease of SARS-CoV-2
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Pengxuan Ren, Changyue Yu, Ruxue Zhang, Tianqing Nie, Qiaoyu Hu, Hui Li, Xianglei Zhang, Xueyuan Zhang, Lu Liu, Wenhao Dai, Jian Li, Yechun Xu, Haixia Su, Leike Zhang, Hong Liu, Shiwei Li, and Fang Bai
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Pharmacology ,History ,Polymers and Plastics ,Organic Chemistry ,Drug Discovery ,General Medicine ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2023
56. Characterization of EST-SSR markers in Curcuma kwangsiensis S. K. Lee & C. F. Liang based on RNA sequencing and its application for phylogenetic relationship analysis and core collection construction
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Jianjun Tan, Dong-Mei Li, Jin-Mei Liu, Yechun Xu, and Yuan-jun Ye
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0106 biological sciences ,0301 basic medicine ,Germplasm ,Genetics ,Breeding program ,Locus (genetics) ,Plant Science ,Biology ,biology.organism_classification ,01 natural sciences ,Genetic analysis ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,Primer (molecular biology) ,Curcuma ,Allele ,Agronomy and Crop Science ,Ecology, Evolution, Behavior and Systematics ,010606 plant biology & botany - Abstract
Curcuma kwangsiensis S. K. Lee & C. F. Liang, a traditional herb in southern China, accumulates substantial amounts of active components, curcuminoids and volatile oil. However, the limited hereditary information and SSR markers have hindered its breeding program and genetic analysis. Here, we examined the transcriptome of C. kwangsiensis using next-generation sequencing (NGS) technology. A dataset with 8.17 Gb of raw reads was generated and assembled into 77,976 unigenes. Moreover, 11,678 EST-SSR markers were screened from transcriptome data. Of the 800 synthesized primer pairs, 486 (60.8%) exhibited successful amplification and 115 (23.7%) were polymorphic. A set of 24 selected markers showed high cross-species transferabilities among 13 Curcuma species. In total, 277 alleles (6–19 alleles per locus) were discovered, and the polymorphic information content (PIC) ranged from 0.496 to 0.905. Based on the results of cluster and structure analyses, the 75 accessions were classified into four major groups with some admixtures. Finally, a core collection (22 accessions) was identified, exhibiting Na, Ne, I, and PIC values with retention rates of 87.7%, 107.8%, 102.5% and 102%, respectively. All these unigenes and EST-SSRs will be useful for germplasm resource evaluation and for diversifying the potential of product derivatives from Curcuma.
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- 2021
57. What coronavirus 3C‐like protease tells us: From structure, substrate selectivity, to inhibitor design
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Hang Xie, Haixia Su, Wenfeng Zhao, Yechun Xu, Muya Xiong, and Qiang Shao
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Polyproteins ,Coronavirus disease 2019 (COVID-19) ,Protein Conformation ,viruses ,medicine.medical_treatment ,coronavirus ,Review Article ,Biology ,medicine.disease_cause ,3C‐like protease ,Antiviral Agents ,Substrate Specificity ,binding modes ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,inhibitors ,Drug Discovery ,Pandemic ,medicine ,Humans ,3c protease ,Protein Structure, Quaternary ,Review Articles ,Coronavirus 3C Proteases ,030304 developmental biology ,Coronavirus ,Pharmacology ,0303 health sciences ,Binding Sites ,Protease ,SARS-CoV-2 ,Drug discovery ,virus diseases ,Substrate (biology) ,Virology ,COVID-19 Drug Treatment ,Drug Design ,030220 oncology & carcinogenesis ,Molecular Medicine ,structure and function - Abstract
The emergence of a variety of coronaviruses (CoVs) in the last decades has posed huge threats to human health. Especially, the ongoing pandemic of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to more than 70 million infections and over 1.6 million of deaths worldwide in the past few months. None of the efficacious antiviral agents against human CoVs have been approved yet. 3C‐like protease (3CLpro) is an attractive target for antiviral intervention due to its essential role in processing polyproteins translated from viral RNA, and its conserved structural feature and substrate specificity among CoVs in spite of the sequence variation. This review focuses on all available crystal structures of 12 CoV 3CLpros and their inhibitors, and intends to provide a comprehensive understanding of this protease from multiple aspects including its structural features, substrate specificity, inhibitor binding modes, and more importantly, to recapitulate the similarity and diversity among different CoV 3CLpros and the structure–activity relationship of various types of inhibitors. Such an attempt could gain a deep insight into the inhibition mechanisms and drive future structure‐based drug discovery targeting 3CLpros.
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- 2021
58. Identification of C270 as a novel site for allosteric modulators of SARS-CoV-2 papain-like protease
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Hangchen Hu, Qian Wang, Haixia Su, Qiang Shao, Wenfeng Zhao, Guofeng Chen, Minjun Li, and Yechun Xu
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The papain-like protease (PLpro) in coronavirus is one of key cysteine proteases responsible for the proteolytic processing of viral polyproteins, and plays an important role in dysregulation of host immune response. PLpro is a promising therapeutic target with a major challenge in inhibitor design due to the restricted S1/S2 sites for two consecutive glycine of substrates. Here we reported the discovery of two activators of the SARS-CoV-2 PLpro from a biochemical screening, and the identification of the unique residue, C270, as an allosteric and covalent regulation site for the activators. This site was also specifically modified by glutathione oxidized, resulting in the S-glutathionylation and activation of the protease. Furthermore, one compound was found to allosterically inhibit the protease by covalent binding to this crucial site. Together, these results elucidated an unrevealed molecular mechanism for allosteric modulation of the protease’s activity, and provided a new strategy for discovery of allosteric inhibitors of the SARS-CoV-2 PLpro.
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- 2022
59. Anti-inflammatory signaling through G protein-coupled receptors
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Qi-wen Liao, Beili Wu, Richard D. Ye, Yunjun Ge, Yechun Xu, and Qiang Zhao
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0301 basic medicine ,Chemokine ,medicine.drug_class ,Inflammation ,Review Article ,Biology ,Anti-inflammatory ,Receptors, G-Protein-Coupled ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Pharmacology (medical) ,Receptors, Lipoxin ,Receptor ,G protein-coupled receptor ,Pharmacology ,Chemotaxis ,General Medicine ,Human physiology ,Receptors, Formyl Peptide ,Cell biology ,Lipoxins ,Molecular Docking Simulation ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Signal transduction ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
G protein-coupled receptors (GPCRs) play important roles in human physiology. GPCRs are involved in immunoregulation including regulation of the inflammatory response. Chemotaxis of phagocytes and lymphocytes is mediated to a great extent by the GPCRs for chemoattractants including myriads of chemokines. Accumulation and activation of phagocytes at the site of inflammation contribute to local inflammatory response. A handful of GPCRs have been found to transduce anti-inflammatory signals that promote resolution of inflammation. These GPCRs interact with selected metabolites of arachdonic acid, such as lipoxins, and of omega-3 essential fatty acids, such as resolvins and protectins. Despite mounting evidence for the in vivo functions of these anti-inflammatory and pro-resolving ligands paired with their respective GPCRs, the underlying signaling mechanisms have not been fully delineated. The present review summarizes what we have learned about these GPCRs, their structures and signaling pathways and the prospect of targeting these receptors for novel anti-inflammatory therapies.
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- 2020
60. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir
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Jingshan Shen, Wenfeng Zhao, Qingya Shen, Sheng-Ce Tao, Hualiang Jiang, Yan Zhang, Minqi Gao, Fulai Zhou, Wanchao Yin, Xiaoxi Wang, He wei Jiang, Dan-Dan Shen, Xiaodong Luan, H. Eric Xu, Yi Jiang, Yechun Xu, Yuan Chao Xie, Shuyang Zhang, Chunyou Mao, Guanghui Tian, Haixia Su, and Shenghai Chang
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Models, Molecular ,0301 basic medicine ,Protein Conformation ,Viral protein ,medicine.drug_class ,Base pair ,viruses ,RNA-dependent RNA polymerase ,Viral Nonstructural Proteins ,Virus Replication ,medicine.disease_cause ,Antiviral Agents ,Betacoronavirus ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Report ,Catalytic Domain ,RNA polymerase ,medicine ,Enzyme Inhibitors ,Alanine ,Coronavirus RNA-Dependent RNA Polymerase ,Multidisciplinary ,SARS-CoV-2 ,Chemistry ,Cryoelectron Microscopy ,Biochem ,RNA ,RNA-Dependent RNA Polymerase ,Virology ,Adenosine Monophosphate ,030104 developmental biology ,Viral replication ,Multiprotein Complexes ,030220 oncology & carcinogenesis ,RNA, Viral ,Antiviral drug ,Primer (molecular biology) ,Reports - Abstract
A wrench in the works of COVID-19 Understanding the inner workings of the virus that causes coronavirus disease 2019 (COVID-19) may help us to disrupt it. Yin et al. focused on the viral polymerase essential for replicating viral RNA. They determined a structure of the polymerase bound to RNA and to the drug remdesivir. Remdesivir mimics an RNA nucleotide building block and is covalently linked to the replicating RNA, which blocks further synthesis of RNA. The structure provides a template for designing improved therapeutics against the viral polymerase. Science , this issue p. 1499
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- 2020
61. Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor
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Xianglei Zhang, Yechun Xu, Y. L. Zhu, Zhen Wang, Xiangrui Jiang, Jingshan Shen, Xingxing Diao, Dafang Zhong, and Qian-Qian Tian
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Male ,0301 basic medicine ,CYP3A ,Metabolite ,Pyrimidinones ,Plasma protein binding ,Pharmacology ,Mass Spectrometry ,Article ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,Species Specificity ,Pharmacokinetics ,Animals ,Cytochrome P-450 CYP3A ,Humans ,Pharmacology (medical) ,Chromatography, High Pressure Liquid ,Active metabolite ,Sulfonamides ,CYP3A4 ,General Medicine ,Metabolism ,Phosphodiesterase 5 Inhibitors ,Macaca fascicularis ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,cGMP-specific phosphodiesterase type 5 ,Microsomes, Liver - Abstract
TPN729 is a novel phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction in men. Our previous study shows that the plasma exposure of metabolite M3 (N-dealkylation of TPN729) in humans is much higher than that of TPN729. In this study, we compared its metabolism and pharmacokinetics in different species and explored the contribution of its main metabolite M3 to pharmacological effect. We conducted a combinatory approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolite identification, and examined pharmacokinetic profiles in monkeys, dogs, and rats following TPN729 administration. A remarkable species difference was observed in the relative abundance of major metabolite M3: i.e., the plasma exposure of M3 was 7.6-fold higher than that of TPN729 in humans, and 3.5-, 1.2-, 1.1-fold in monkeys, dogs, and rats, respectively. We incubated liver S9 and liver microsomes with TPN729 and CYP3A inhibitors, and demonstrated that CYP3A was responsible for TPN729 metabolism and M3 formation in humans. The inhibitory activity of M3 on PDE5 was 0.78-fold that of TPN729 (The IC(50) values of TPN729 and M3 for PDE5A were 6.17 ± 0.48 and 7.94 ± 0.07 nM, respectively.). The plasma protein binding rates of TPN729 and M3 in humans were 92.7% and 98.7%, respectively. It was astonishing that the catalyzing capability of CYP3A4 in M3 formation exhibited seven-fold disparity between different species. M3 was an active metabolite, and its pharmacological contribution was equal to that of TPN729 in humans. These findings provide new insights into the limitation and selection of animal model for predicting the clinical pharmacokinetics of drug candidates metabolized by CYP3A4.
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- 2020
62. In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP–AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing
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Yechun Xu, Minjun Li, Xiaojing Yuan, Muya Xiong, Hongbin Sun, and Wenfeng Zhao
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Thermal shift assay ,General Chemical Engineering ,In silico ,Library and Information Sciences ,01 natural sciences ,Molecular Docking Simulation ,0103 physical sciences ,Humans ,Nucleotide ,Enzyme Inhibitors ,chemistry.chemical_classification ,Virtual screening ,Cyclic GMP-AMP synthase ,010304 chemical physics ,Reproducibility of Results ,General Chemistry ,Nucleotidyltransferases ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,Computer Science Applications ,010404 medicinal & biomolecular chemistry ,chemistry ,Docking (molecular) ,Nucleotides, Cyclic - Abstract
Cyclic GMP-AMP synthase (cGAS) has been recently uncovered to be a promising therapeutic target for immune-associated diseases. Until now, only a few inhibitors have been identified through high-throughput screening campaigns. Here, we reported the discovery of novel inhibitors for the catalytic domain of human cGAS (h-cGASCD) by virtual screening for the first time. To generate a reliable docking mode, we first obtained a high-resolution crystal structure of h-cGASCD in complex with PF-06928215, a known inhibitor of h-cGAS, followed by molecular dynamics simulations on this complex structure. Four fragment hits were identified by the virtual screening together with a thermal shift assay. The crystal structures of these four compounds in complex with h-cGASCD were subsequently determined, and the binding modes of the compounds were similar to those predicted by molecular docking, supporting the reliability of the docking model. In addition, an enzyme activity assay identified compound 18 (IC50 = 29.88 ± 3.20 μM) from the compounds predicted by the virtual screening. A similarity search of compound 18 followed by a second virtual screening led to the discovery of compounds S2 (IC50 = 13.1 ± 0.09 μM) and S3 (IC50 = 4.9 ± 0.26 μM) as h-cGAS inhibitors with improved potency. Therefore, the present study not only provides the validated hit compounds for further development of h-cGAS inhibitors but also demonstrates a cross-validation study of virtual screening, in vitro experimental assays, and crystal structure determination.
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- 2020
63. Exploration of Fragment Binding Poses Leading to Efficient Discovery of Highly Potent and Orally Effective Inhibitors of FABP4 for Anti-inflammation
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Xianglei Zhang, Hang Xie, Xiaojing Yuan, Hui-Xia Dou, Yechun Xu, Naixia Zhang, Yi Zou, Guofeng Chen, Haixia Su, and Minjun Li
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Male ,Drug ,media_common.quotation_subject ,Treatment outcome ,Anti-Inflammatory Agents ,Administration, Oral ,Pharmacology ,Fatty Acid-Binding Proteins ,01 natural sciences ,Protein Structure, Secondary ,3T3 cells ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Protein structure ,Fragment (logic) ,Drug Discovery ,medicine ,Animals ,Humans ,030304 developmental biology ,media_common ,Inflammation ,Mice, Inbred ICR ,0303 health sciences ,Dose-Response Relationship, Drug ,Chemistry ,Binding protein ,Biphenyl Compounds ,Anti inflammation ,3T3 Cells ,Protein Structure, Tertiary ,0104 chemical sciences ,Mice, Inbred C57BL ,010404 medicinal & biomolecular chemistry ,Treatment Outcome ,medicine.anatomical_structure ,Pyrazoles ,Molecular Medicine ,Caco-2 Cells ,Lead compound ,Protein Binding - Abstract
Fatty-acid binding protein 4 (FABP4) is a promising therapeutic target for immunometabolic diseases, while its potential for systemic inflammatory response syndrome treatment has not been explored. Here, a series of 2-(phenylamino)benzoic acids as novel and potent FABP4 inhibitors are rationally designed based on an interesting fragment that adopts multiple binding poses within FABP4. A fusion of these binding poses leads to the design of compound 3 with an ∼460-fold improvement in binding affinity compared to the initial fragment. A subsequent structure-aided optimization upon 3 results in a promising lead (17) with the highest binding affinity among all the inhibitors, exerting a significant anti-inflammatory effect in cells and effectively attenuating a systemic inflammatory damage in mice. Our work therefore presents a good example of lead compound discovery derived from the multiple binding poses of a fragment and provides a candidate for development of drugs against inflammation-related diseases.
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- 2020
64. Differentially fed six‐beam switchable reconfigurable antenna
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Yechun Xu, Liao Shaowei, Guiping Jin, Ju Yang, and Miao-Lan Li
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Physics ,Reconfigurable antenna ,business.industry ,020208 electrical & electronic engineering ,020206 networking & telecommunications ,02 engineering and technology ,Antenna efficiency ,law.invention ,Azimuth ,Optics ,law ,0202 electrical engineering, electronic engineering, information engineering ,Dipole antenna ,Electrical and Electronic Engineering ,Reflection coefficient ,Antenna (radio) ,business ,Beam (structure) ,Ground plane - Abstract
Differentially fed six-beam switchable reconfigurable antenna is proposed in this study. The antenna consists of radiators, parasitic elements, cross-shaped feeding network and the ground plane. The radiators are formed by two pairs of gear-shaped cross dipoles. By changing the excitation differential ports to drive one of two pairs of dipoles, and by enabling different reflectors, the beam can be switched to point to six different directions with different zenith and azimuth angles. For all the beam directions, the proposed antenna can obtain -10 dB differential reflection coefficient of 20.8% operating from 3.01 to 3.76 GHz, a high average gain of 7.6 dBi and radiation efficiency of 80%.
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- 2020
65. Structural basis of ligand binding modes at the human formyl peptide receptor 2
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Xin Zong, Cuiying Yi, Hui Zhang, Yechun Xu, Qiang Zhao, Limin Ma, Yunjun Ge, Tong Chen, Beili Wu, Gye Won Han, Muya Xiong, Mu Wang, and Richard D. Ye
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0301 basic medicine ,Agonist ,Protein Conformation ,medicine.drug_class ,Science ,General Physics and Astronomy ,Peptide ,Ligands ,Article ,General Biochemistry, Genetics and Molecular Biology ,Formyl peptide receptor 2 ,Structure-Activity Relationship ,03 medical and health sciences ,0302 clinical medicine ,G protein-coupled receptors ,medicine ,Humans ,Amino Acid Sequence ,Receptors, Lipoxin ,lcsh:Science ,Peptide sequence ,X-ray crystallography ,G protein-coupled receptor ,chemistry.chemical_classification ,Binding Sites ,Multidisciplinary ,Formyl peptide receptor ,Chemistry ,Chemotaxis ,General Chemistry ,Ligand (biochemistry) ,Receptors, Formyl Peptide ,Molecular Docking Simulation ,N-Formylmethionine Leucyl-Phenylalanine ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Biophysics ,lcsh:Q ,Signal Transduction - Abstract
The human formyl peptide receptor 2 (FPR2) plays a crucial role in host defense and inflammation, and has been considered as a drug target for chronic inflammatory diseases. A variety of peptides with different structures and origins have been characterized as FPR2 ligands. However, the ligand-binding modes of FPR2 remain elusive, thereby limiting the development of potential drugs. Here we report the crystal structure of FPR2 bound to the potent peptide agonist WKYMVm at 2.8 Å resolution. The structure adopts an active conformation and exhibits a deep ligand-binding pocket. Combined with mutagenesis, ligand binding and signaling studies, key interactions between the agonist and FPR2 that govern ligand recognition and receptor activation are identified. Furthermore, molecular docking and functional assays reveal key factors that may define binding affinity and agonist potency of formyl peptides. These findings deepen our understanding about ligand recognition and selectivity mechanisms of the formyl peptide receptor family., Formyl peptide receptors (FPRs) are GPCRs that play important roles in transducing chemotactic signals in phagocytes and mediating host-defense and inflammatory responses. Here the authors present the 2.8 Å crystal structure of human FPR2 in complex with the peptide agonist WKYMVm and in combination with molecular docking, ligand-binding and signalling assays provide further insights into the binding modes of FPR2 to both non-formyl and formyl peptides.
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- 2020
66. Differential Frequency-Reconfigurable Antenna Based on Dipoles for Sub-6 GHz 5G and WLAN Applications
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Yechun Xu, Ju Yang, Guiping Jin, Chuhong Deng, and Shaowei Liao
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Physics ,Reconfigurable antenna ,Bandwidth (signal processing) ,020206 networking & telecommunications ,Near and far field ,02 engineering and technology ,Radiation ,Topology ,law.invention ,Dipole ,law ,0202 electrical engineering, electronic engineering, information engineering ,Electrical and Electronic Engineering ,Electrical impedance ,5G ,Diode - Abstract
A new differential frequency-reconfigurable antenna based on dipoles is presented in this letter. The basic structure of the proposed antenna consists of two pairs of vertical arms forming two dipoles, the feeding structure, mode switching structure, and p-i-n diodes. By switching “ on ” and “ off ” p-i-n diodes, the antenna can resonate at two states, and thus work centered at 3.5 and 5.5 GHz, respectively. Though the two states correspond to different resonant modes, the effective radiation parts are the same and the mode switching structure will not contribute to the far field for both states. This results in similar radiation patterns for both states. Besides, the proposed antenna is also simple in structure and wide in bandwidth. The measured −10 dB impedance bandwidths are 2.89–4.07 GHz (33%) and 5.1–6.19 GHz (19.8%) for the two states, respectively.
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- 2020
67. Diterpenoids from the Root Bark of Pinus massoniana and Evaluation of Their Phosphodiesterase Type 4D Inhibitory Activity
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Xianglei Zhang, Wei-Min Zhao, Xiaomin Luo, Xiaoyu Ding, Yifan Fu, Yechun Xu, Xingcheng Shao, and Jihui Zhao
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Pharmacology ,Pinus massoniana ,biology ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Pharmaceutical Science ,Phosphodiesterase ,biology.organism_classification ,Inhibitory postsynaptic potential ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,visual_art ,Drug Discovery ,visual_art.visual_art_medium ,Ic50 values ,Molecular Medicine ,Bark - Abstract
Thirty-two diterpenoids were obtained from the root bark of Pinus massoniana, and, among them, five compounds (pinmassins A-E) were identified as undescribed analogues. Spectroscopic methods, X-ray single-crystal diffraction analysis, and ECD calculations were applied to establish the structure of the new isolates. Pinmassin D (4) and abieta-8,11,13,15-tetraen-18-oic acid (23) showed moderate phosphodiesterase type 4D (PDE4D) inhibitory effects with IC50 values of 2.8 ± 0.18 and 3.3 ± 0.50 μM, respectively, and their binding modes were investigated by a molecular docking study.
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- 2020
68. Dual‐polarised high‐gain triple‐band differential antenna for WLAN and Sub‐6 GHz 5G applications
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Yechun Xu, Guangjie Zeng, Guiping Jin, Ju Yang, and Liao Shaowei
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Physics ,business.product_category ,business.industry ,Frequency band ,020208 electrical & electronic engineering ,020206 networking & telecommunications ,02 engineering and technology ,Directivity ,Wireless access point ,Intermediate frequency ,Filter (video) ,0202 electrical engineering, electronic engineering, information engineering ,Radiator (engine cooling) ,Optoelectronics ,Electrical and Electronic Engineering ,Antenna (radio) ,business ,Electrical impedance - Abstract
A new dual-polarised high-gain triple-band differential-fed antenna is proposed in this study. The antenna adopts a differential feeding scheme, in which a high-frequency radiator for 3.5 GHz Sub-6 GHz 5G band and 5 GHz WLAN band, and two pairs of low-frequency radiators for 2.45 GHz WLAN band are effectively combined to obtain multiband operation. To filter out unwanted frequency band, four half-wavelength slots are introduced to generate a notch band between 3.8 and 4.8 GHz. Experimental results show that the proposed antenna achieves 10-dB impedance bandwidths of 2.37-2.61 GHz for the low-frequency band, 3.27-3.76 GHz for the intermediate frequency band, and 4.87-5.98 GHz for the high-frequency band. The gains of the antenna are all above 8.0 dBi for all the three bands. The antenna exhibits a good directivity and low cross-polarisation level (below -20 dB); thus it is a good candidate for WLAN and Sub-6 GHz 5G wireless access point systems.
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- 2020
69. Dipyridamole interacts with the N-terminal domain of HSP90 and antagonizes the function of the chaperone in multiple cancer cell lines
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Jing, Gao, Chen, Zhou, Yan, Zhong, Li, Shi, Xuanyang, Luo, Haixia, Su, Minjun, Li, Yechun, Xu, Naixia, Zhang, and Hu, Zhou
- Subjects
Pharmacology ,Biochemistry - Abstract
Molecular chaperone HSP90 has been considered as a promising target for anti-cancer drug development for years. However, due to the heat shock response induced by the ATP competitive inhibitors against HSP90, the therapeutic efficacies of the compounds are compromised, which consequently restricts the clinical use of HSP90-targeted inhibitors. Therefore, there is a need to discover novel HSP90-targeted modulators which exhibit acceptable inhibition activity against the chaperone and do not induce significant heat shock response in the meantime. Here in this study, we firstly developed a tip-based affinity selection-mass spectrometry platform with optimized experimental conditions/parameters for HSP90-targeted active compound screening, and then applied it to fish out inhibitors against HSP90 from a collection of 2,395 compounds composed of FDA-approved drugs and drug candidates. Dipyridamole, which acts as an anti-thrombotic agent by modulating multiple targets and has a long history of safe use, was identified to interact with HSP90's N-terminal domain. The following conducted biophysical and biochemical experiments demonstrated that Dipyridamole could bind to HSP90's ATP binding pocket and function as an ATP competitive inhibitor of the chaperone. Finally, cellular-based assays including CESTA, cell viability assessment and proteomic analysis etc. were performed to evaluate whether the interaction between HSP90 and Dipyridamole contributes to the anti-tumor effects of the compound. We then found that Dipyridamole inhibits the growth and proliferation of human cancer cells by downregulating cell cycle regulators and upregulating apoptotic cell signaling, which are potentially mediated by the binding of Dipyridamole to HSP90 and to PDEs (phosphodiesterases), respectively.
- Published
- 2023
70. Potent and Selective RIPK1 Inhibitors Targeting Dual‐Pockets for the Treatment of Systemic Inflammatory Response Syndrome and Sepsis
- Author
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Tao Yang, Binbin Zhang, Haixia Su, Tianqing Nie, Yechun Xu, Bing Zhou, Huimin Lu, Xiangbo Yang, Chen Fan, Hang Xie, and Wei Tang
- Subjects
Sulfonamides ,business.industry ,Kinase ,Drug discovery ,Necroptosis ,Allosteric regulation ,Organ dysfunction ,Imidazoles ,General Chemistry ,Thiophenes ,General Medicine ,Pharmacology ,medicine.disease ,Catalysis ,Systemic inflammatory response syndrome ,Sepsis ,RIPK1 ,Medicine ,medicine.symptom ,business - Abstract
Sepsis, characterized with high risk of life-threatening organ dysfunction, represents a major cause of health loss and the World Health Organization (WHO) labelled sepsis as the most urgent unmet medical need in 2017. The emerging biological understanding of the role of RIPK1 in sepsis has opened up an exciting opportunity to explore potent and selective RIPK1 inhibitors as an effective therapeutic strategy for SIRS and sepsis therapy. Herein, we have synthesized a class of highly potent dual-mode RIPK1 inhibitors occupying both the allosteric and the ATP binding pockets, exemplified by compound 21 (ZB-R-55) which is about 10-fold more potent than GSK2982772, and exhibits excellent kinase selectivity, good oral pharmacokinetics and good therapeutic effects in the LPS-induced sepsis model, suggesting that compound ZB-R-55 is a highly promising preclinical candidate.
- Published
- 2021
71. Novel thieno[2,3-b]quinoline-procaine hybrid molecules: A new class of allosteric SHP-1 activators evolved from PTP1B inhibitors
- Author
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Lei Xu, Xuyang Mu, Minmin Liu, Zhijia Wang, Chao Shen, Qianwen Mu, Bo Feng, Yechun Xu, Tingjun Hou, Lixin Gao, Haini Jiang, Jia Li, Yubo Zhou, and Wenlong Wang
- Subjects
General Chemistry - Published
- 2022
72. Structure-based design of a novel inhibitor of the ZIKA virus NS2B/NS3 protease
- Author
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Yanchao Xiong, Fei Cheng, Junyi Zhang, Haixia Su, Hangchen Hu, Yi Zou, Minjun Li, and Yechun Xu
- Subjects
Protein Conformation ,Zika Virus Infection ,Organic Chemistry ,Zika Virus ,Viral Nonstructural Proteins ,Ligands ,Antiviral Agents ,Biochemistry ,Drug Discovery ,Humans ,Protease Inhibitors ,Molecular Biology ,Peptide Hydrolases ,Protein Binding - Abstract
Zika virus (ZIKV) has been a serious public health problem, and there is no vaccine or drug approved for the prevention or treatment of ZIKV yet. The ZIKV NS2B/NS3 protease plays an important role in processing the virus precursor polyprotein and is thus a promising target for antiviral drugs development. In order to discover novel inhibitors of this protease, we carried out a fragment-based hit screening and characterized protein-inhibitor interactions using the X-ray crystallography together with isothermal titration calorimetry. We reported two high-resolution crystal structures of the protease (bZiPro
- Published
- 2022
73. Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy
- Author
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Fangmin Chen, Bo Hou, Yechun Xu, Tianliang Li, Shunan Zhang, Zhiai Xu, Jiayi Ye, Muya Xiong, and Haijun Yu
- Subjects
Tumor microenvironment ,Chemistry ,medicine.medical_treatment ,Immunogenicity ,Photodynamic therapy ,Prodrug ,Immune system ,Cancer immunotherapy ,Interferon ,medicine ,Cancer research ,Immunogenic cell death ,General Pharmacology, Toxicology and Pharmaceutics ,medicine.drug - Abstract
Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.
- Published
- 2021
74. Front Cover Image, Volume 41, Issue 4
- Author
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Muya Xiong, Haixia Su, Wenfeng Zhao, Hang Xie, Qiang Shao, and Yechun Xu
- Subjects
Pharmacology ,Drug Discovery ,Molecular Medicine - Published
- 2021
75. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease
- Author
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Minjun Li, Gengfu Xiao, Wenfeng Zhao, Leike Zhang, Jia Liu, Jingshan Shen, Lu Feng, Yumin Zhang, Yang Ye, Weijuan Shang, Qingxing Wang, Qiang Shao, Haixia Su, Chang-Qiang Ke, Hang Xie, Xiangrui Jiang, Yechun Xu, Hualiang Jiang, and Sheng Yao
- Subjects
0301 basic medicine ,Science ,medicine.medical_treatment ,Coronavirus Papain-Like Proteases ,General Physics and Astronomy ,Medicinal chemistry ,Molecular Dynamics Simulation ,Pyrogallol ,Viral Nonstructural Proteins ,Ligands ,medicine.disease_cause ,Antiviral Agents ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,Protease Inhibitors ,Mode of action ,Coronavirus 3C Proteases ,X-ray crystallography ,Coronavirus ,Flavonoids ,Multidisciplinary ,Protease ,SARS-CoV-2 ,Drug discovery ,General Chemistry ,Combinatorial chemistry ,COVID-19 Drug Treatment ,Kinetics ,HEK293 Cells ,030104 developmental biology ,chemistry ,Viral infection ,Covalent bond ,Drug Design ,030220 oncology & carcinogenesis ,Myricetin ,Structural biology ,Cysteine - Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands., SARS-CoV-2 3CL protease (3CLpro) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CLpro, and they solve crystal structures of 3CLpro with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.
- Published
- 2021
76. Cocktail polysaccharides isolated from Ecklonia kurome against the SARS-CoV-2 infection
- Author
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Yechun Xu, Yi Zang, Xia Chen, Shihai Zhang, Xinwen Chen, Ding Kan, Hao Sun, Can Jin, Yaqi Ding, Zhenyun Du, Minbo Su, Rongjuan Pei, Haixia Su, Jia Li, Chunfan Huang, Bo Zhang, and Meixia Li
- Subjects
Ecklonia kurome ,Polymers and Plastics ,High-throughput screening ,Heparan sulfate ,1-Cyclo-hexyl-3-(2-mopholinoethyl) carbodiimidemetho-p-toluenesulfonate ,Polysaccharide ,Article ,Ecklonia kurome Okam ,Virus ,Acetone ,3CL protease ,chemistry.chemical_compound ,Polysaccharides ,Materials Chemistry ,Humans ,Receptor ,Sodium borohydride ,chemistry.chemical_classification ,biology ,SARS-CoV-2 ,Chemistry ,Alginate ,Organic Chemistry ,Fucan ,COVID-19 ,Dimethyl sulfoxide ,Virus Internalization ,Guluronic acid ,biology.organism_classification ,Seaweed ,Brown algae ,Molecular Docking Simulation ,Enzyme ,Biochemistry ,Angiotensin converting enzyme 2 (ACE2) ,Deuterium oxide ,Mannuronic acid - Abstract
Previous researches suggested that polysaccharides from brown algae had anti-virus activity. We hypothesized that nature polysaccharide from marine plants might have the effect on anti-SARS-CoV-2 activity. By high throughput screening to target 3CLpro enzyme using polysaccharides library, we discover a crude polysaccharide 375 from seaweed Ecklonia kurome blocked 3CLpro enzymatic activity and shows good anti-SARS-CoV-2 infection activity in cell. Further, we show that homogeneous polysaccharide 37502 from the 375 may bind to 3CLpro well and disturb spike protein binding to ACE2 receptor. The structure characterization uncovers that 37502 is alginate. These results imply that the bioactivities of 375 on SARS-CoV-2 may target multiple key molecules implicated in the virus infection and replication. The above results suggest that 375 may be a potential drug candidate against SARS-CoV-2., Graphical abstract Unlabelled Image
- Published
- 2021
77. Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design
- Author
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Zhaoping Xiong, Bo Liu, Yechun Xu, Fei Li, Meiyu Geng, Yuanyang Zhou, Jia Liu, Xiaowei Wu, Qiufeng Liu, Yulan Wang, Rongrong Cui, Bao Wang, Yang Dai, Minjia Tan, Xiaoqin Tan, Jing Ai, Mingyue Zheng, Hong Liu, Chunpu Li, Hualiang Jiang, and Mingrui Zhu
- Subjects
0303 health sciences ,Virtual screening ,biology ,Drug discovery ,Chemistry ,FGFR Inhibition ,hERG ,Drug design ,Computational biology ,01 natural sciences ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,Docking (molecular) ,Fibroblast growth factor receptor ,Drug Discovery ,biology.protein ,Molecular Medicine ,Structure–activity relationship ,030304 developmental biology - Abstract
Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15, which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15 as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery.
- Published
- 2019
78. Structural basis for ligand recognition of the human thromboxane A2 receptor
- Author
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Qiang Zhao, Xiaojing Yuan, Hengxin Fan, Shuanghong Chen, Yechun Xu, Weiliang Xia, Shuo Han, Beili Wu, and Hui Zhang
- Subjects
0303 health sciences ,Ligand ,Chemistry ,030302 biochemistry & molecular biology ,Mutagenesis ,Prostanoid ,Cell Biology ,03 medical and health sciences ,chemistry.chemical_compound ,Thromboxane A2 ,Protein structure ,Biophysics ,medicine ,Ramatroban ,Binding site ,Receptor ,Molecular Biology ,030304 developmental biology ,medicine.drug - Abstract
Stimulated by thromboxane A2, an endogenous arachidonic acid metabolite, the thromboxane A2 receptor (TP) plays a pivotal role in cardiovascular homeostasis, and thus is considered as an important drug target for cardiovascular disease. Here, we report crystal structures of the human TP bound to two nonprostanoid antagonists, ramatroban and daltroban, at 2.5 A and 3.0 A resolution, respectively. The TP structures reveal a ligand-binding pocket capped by two layers of extracellular loops that are stabilized by two disulfide bonds, limiting ligand access from the extracellular milieu. These structures provide details of interactions between the receptor and antagonists, which help to integrate previous mutagenesis and SAR data. Molecular docking of prostanoid-like ligands, combined with mutagenesis, ligand-binding and functional assays, suggests a prostanoid binding mode that may also be adopted by other prostanoid receptors. These insights into TP deepen our understanding about ligand recognition and selectivity mechanisms of this physiologically important receptor. Structures of the human thromboxane A2 receptor, a member of the prostanoid family of G-protein-coupled receptors, in complex with two synthetic antagonists reveal that ligands access the ligand-binding pocket from the plane of the lipid bilayer.
- Published
- 2018
79. Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2
- Author
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Xiaodong Luan, Weijuan Shang, Hualiang Jiang, Yechun Xu, Leike Zhang, Gengfu Xiao, Yuanchao Xie, H. Eric Xu, Yumin Zhang, Guanghui Tian, Jia Li, Haji Akber Aisa, Shuyang Zhang, Jingshan Shen, Wanchao Yin, and Zhen Wang
- Subjects
2019-20 coronavirus outbreak ,Cell biology ,Alanine ,Coronavirus disease 2019 (COVID-19) ,Molecular biology ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Clinical Studies as Topic ,Immunology ,Administration, Oral ,Biology ,Virology ,Antiviral Agents ,Adenosine Monophosphate ,Rats ,COVID-19 Drug Treatment ,chemistry.chemical_compound ,Mice ,chemistry ,Animals ,Humans ,Letter to the Editor ,Derivative (chemistry) - Published
- 2021
80. Structural characterization of cocktail-like targeting polysaccharides from Ecklonia kurome Okam and their anti-SARS-CoV-2 activities invitro
- Author
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Minbo Su, Xia Chen, Rongjuan Pei, Jia Li, Xinwen Chen, Chunfan Huang, Yaqi Ding, Yechun Xu, Kan Ding, Can Jin, Zhenyun Du, Bo Zhang, Shihai Zhang, Hao Sun, Meixia Li, and Yi Zhang
- Subjects
chemistry.chemical_classification ,Ecklonia kurome ,biology ,Rhamnose ,Mannose ,Heparan sulfate ,Polysaccharide ,biology.organism_classification ,Fucose ,chemistry.chemical_compound ,Enzyme ,chemistry ,Biochemistry ,Galactose - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent responsible for the worldwide coronavirus disease 2019 (COVID-19) outbreak. Investigation has confirmed that polysaccharide heparan sulfate can bind to the spike protein and block SARS-CoV-2 infection. Theoretically, similar structure of nature polysaccharides may also have the impact on the virus. Indeed, some marine polysaccharide has been reported to inhibit SARS-Cov-2 infection in vitro, however the convinced targets and mechanism are still vague. By high throughput screening to target 3CLpro enzyme, a key enzyme that plays a pivotal role in the viral replication and transcription using nature polysaccharides library, we discover the mixture polysaccharide 375 from seaweed Ecklonia kurome Okam completely block 3Clpro enzymatic activity (IC50, 0.48 µM). Further, the homogeneous polysaccharide 37502 from the 375 may bind to 3CLpro molecule well (kD value : 4.23 × 10−6). Very interestingly, 37502 also can potently disturb spike protein binding to ACE2 receptor (EC50, 2.01 µM). Importantly, polysaccharide 375 shows good anti-SARS-CoV-2 infection activity in cell culture with EC50 values of 27 nM (99.9% inhibiting rate at the concentration of 20 µg/mL), low toxicity (LD50: 136 mg/Kg on mice). By DEAE ion-exchange chromatography, 37501, 37502 and 37503 polysaccharides are purified from native 375. Bioactivity test show that 37501 and 37503 may impede SARS-Cov-2 infection and virus replication, however their individual impact on the virus is significantly less that of 375. Surprisingly, polysaccharide 37502 has no inhibition effect on SARS-Cov-2. The structure study based on monosaccharide composition, methylation, NMR spectrum analysis suggest that 375 contains guluronic acid, mannuronic acid, mannose, rhamnose, glucouronic acid, galacturonic acid, glucose, galactose, xylose and fucose with ratio of 1.86 : 9.56 : 6.81 : 1.69 : 1.00 : 1.75 : 1.19 : 11.06 : 4.31 : 23.06. However, polysaccharide 37502 is an aginate which composed of mannuronic acid (89.3 %) and guluronic acid (10.7 %), with the molecular weight (Mw) of 27.9 kDa. These results imply that mixture polysaccharides 375 works better than the individual polysaccharide on SARS-Cov-2 may be the cocktail-like polysaccharide synergistic function through targeting multiple key molecules implicated in the virus infection and replication. The results also suggest that 375 may be a potential drug candidate against SARS-CoV-2.
- Published
- 2021
81. Discovery of novel inhibitors against main protease (Mpro) of SARS-CoV-2 via virtual screening and biochemical evaluation
- Author
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Zhili Zuo, Li Zhang, Yu Lei, Bin Liu, Hang Xie, Yechun Xu, and Sheng Guo
- Subjects
3CLpro, 3C-like protease ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,01 natural sciences ,Biochemistry ,MERS-CoV, middle east respiratory syndrome coronavirus ,Docking (dog) ,PLP, papain-like proteases ,PAINS, pan assay interference compounds ,Drug Discovery ,BBB, blood brain barrier penetration ,PDB, protein data bank ,Pathogen ,RMSD, root mean square difference ,Coronavirus 3C Proteases ,media_common ,ORF, open reading frame genes ,HCoV-229E, Human coronavirus 229E ,Chemistry ,HIA, human intestinal absorption ,COVID-19, corona virus disease 2019 ,N, Nucleocapsid protein ,Molecular Docking Simulation ,DS 4.0, Discovery Studio 4.0 ,Biochemical evaluation ,Virtual screening ,Drug ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,media_common.quotation_subject ,HCoV-NL63, Human coronavirus NL63 ,Computational biology ,SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 ,Antiviral Agents ,Article ,ER, endoplasmic reticulum ,E, envelope protein ,HCoV-OC43, Human coronavirus OC43 ,medicine ,Humans ,UTR, untranslated regions ,Protease Inhibitors ,Molecular Biology ,ComputingMethodologies_COMPUTERGRAPHICS ,nsps, non-structural proteins ,Protease ,pp1ab, polyprotein 1ab ,S, spike glycoprotein ,010405 organic chemistry ,SARS-CoV-2 ,pp1a, polyprotein 1a ,Organic Chemistry ,0104 chemical sciences ,Mpro, main protease ,010404 medicinal & biomolecular chemistry ,M, membrane protein ,Main protease ,IC50, Half maximal inhibitory concentration ,HCoV-HKU1, Human coronavirus Hong Kong University 1 ,CYP450, cytochrome P450 - Abstract
Graphical abstract, SARS-CoV-2 is the pathogen that caused the global COVID-19 outbreak in 2020. Promising progress has been made in developing vaccines and antiviral drugs. Antivirals medicines are necessary complements of vaccines for post-infection treatment. The main protease (Mpro) is an extremely important protease in the reproduction process of coronaviruses which cleaves pp1ab over more than 11 cleavage sites. In this work, two active main protease inhibitors were found via docking-based virtual screening and bioassay. The IC50 of compound VS10 was 0.20 μM, and the IC50 of compound VS12 was 1.89 μM. The finding in this work can be helpful to understand the interactions of main protease and inhibitors. The active candidates could be potential lead compounds for future drug design.
- Published
- 2020
82. Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment
- Author
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Heng Li, Chen Fan, Hui-Xia Dou, Xianglei Zhang, Zhanni Gu, Qianwen Mu, Rui Zhang, Yechun Xu, Wei Tang, Jian Li, Dong Guangyu, Haixia Su, Qiukai Lu, and Hong Liu
- Subjects
Drug ,Lipopolysaccharides ,Models, Molecular ,media_common.quotation_subject ,Inflammation ,Pharmacology ,Crystallography, X-Ray ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Psoriasis ,Tetrahydroisoquinolines ,Drug Discovery ,medicine ,Animals ,Humans ,Cyclic adenosine monophosphate ,Calcipotriol ,030304 developmental biology ,media_common ,chemistry.chemical_classification ,0303 health sciences ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Tetrahydroisoquinoline ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,General Medicine ,medicine.disease ,Small molecule ,0104 chemical sciences ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Enzyme ,RAW 264.7 Cells ,Drug Design ,Female ,Phosphodiesterase 4 Inhibitors ,medicine.symptom - Abstract
Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis.
- Published
- 2020
83. A Planar Differential Dual Helix Antenna for 5G Millimeter-Wave Applications
- Author
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Yechun Xu, Shaowei Liao, Ju Yang, and Guiping Jin
- Subjects
Optics ,Planar ,Materials science ,business.industry ,Bandwidth (signal processing) ,Impedance matching ,Helical antenna ,Antenna (radio) ,Polarization (waves) ,business ,Electrical impedance ,Stripline - Abstract
A new planar differential helix antenna for 5G milli-meter-wave applications is proposed in this paper. The proposed antenna has a simple rotational symmetrical planar structure fed by strip line, which is printed on one substrate. The width of the helix are gradually increasing to improve the RHCP gain. A step ground is used to obtain a better impedance matching. Furthermore, to enhance the vertical polarization and thus improve CP gain, parasitic unit directors formed by metallized via-holes and printed stripes, are introduced. The simulated results show that the −10-dB impedance bandwidth ranges from 24GHz to 30.9GHz (24.6%), and the 3-dB axial ratio bandwidth is from 23.8GHz to 29.1GHz (20%). The proposed antenna features simple structure, low cost and good performance, thus it has a good application prospect in 5G millimeter-wave applications.
- Published
- 2020
84. Single Ridged Waveguide Based Resonant Slotted Antenna Array for Millimeter Wave Radar Application
- Author
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Yechun Xu, Ju Yang, Shaowei Liao, and Guiping Jin
- Subjects
Waveguide (electromagnetism) ,Materials science ,business.industry ,Radiation pattern ,law.invention ,Antenna array ,Optics ,law ,Extremely high frequency ,Radar ,Antenna (radio) ,business ,Electrical impedance ,Beam (structure) - Abstract
A new single ridged waveguide based resonant slotted antenna array for millimeter wave radar application is proposed. The single ridged waveguide is formed by PCB substrate with upper copper foil at the bottom and aluminum structure at the top. Resonant slots are placed along the centerline of the single ridged waveguide's broad wall to obtain a stable and symmetric radiation pattern. By changing the depths at both sides of the ridge, electric neutral plane shifts from the centerline and the current can excite the resonant slot leading to radiation. A protype is designed, and the impedance bandwidth is from 75.94 GHz to 81.21GHz (6.7%). The sidelobes level is lower than 25dB within the entire bandwidth. Horizontal beam angle is ±62°. and vertical beam deviation angle is ±2°. Moreover, the proposed antenna is easy fabrication, high efficiency (95%) and low cost.
- Published
- 2020
85. Segment Descriptor Enabling Prediction of Electronic Properties and Photocatalytic Hydrogen Evolution Rate of Alternating Conjugated Copolymers Based on Machine Learning
- Author
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Bo Li, Yechun Xu, Chen J, Qiu-Shi Ma, Cheng-Wei Ju, and Lei Zhang
- Subjects
Segment descriptor ,Materials science ,Photocatalysis ,Copolymer ,Hydrogen evolution ,Nanotechnology ,Conjugated system ,Electronic properties - Abstract
Alternating conjugated copolymers have been regarded as promising candidates for photocatalytic hydrogen evolution due to the adjustability of their molecular structures and electronic properties. In this work, machine learning (ML) models with molecular fingerprint of segment descriptors (SD) have been successfully constructed to promote the accurate and universal prediction of electronic properties such as electron affinity, ionization potential and optical bandgap. Moreover, without any experimental values, a high-performance prediction classifier model toward photocatalytic hydrogen production of alternating copolymers has been developed with high accuracy (real-test accuracy = 0.91). Consequently, our results demonstrate accurate regression and classification models to disclose valuable influencing factors concerning hydrogen evolution rate (HER) of alternating copolymers.
- Published
- 2020
86. Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach
- Author
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Minjun Li, Ruimin Huang, Yishen Liu, Wenwei Xu, Jianhua Shen, Kai Wang, Chengyuan Peng, Yu Zhang, Jing Gao, Hangchen Hu, Hu Zhou, Yechun Xu, and Fubao Huang
- Subjects
Boron Compounds ,Models, Molecular ,Molecular Conformation ,01 natural sciences ,Serine ,03 medical and health sciences ,Phospholipase A2 ,Drug Discovery ,Humans ,Cysteine ,Enzyme Inhibitors ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Ligand ,Drug discovery ,Combinatorial chemistry ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Enzyme ,HEK293 Cells ,chemistry ,Covalent bond ,1-Alkyl-2-acetylglycerophosphocholine Esterase ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Selectivity - Abstract
Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.
- Published
- 2020
87. Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro
- Author
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Jianping Zuo, Fang Bai, Leike Zhang, Mei-na Gao, Minjun Li, Hong Liu, Sheng Yao, Weijuan Shang, Wenfeng Zhao, Jia Liu, Kunqian Yu, Hualiang Jiang, Yan Wu, Hang Xie, Yechun Xu, Wei Tang, Haixia Su, Chang-Qiang Ke, Yang Ye, and Jingshan Shen
- Subjects
Protease ,Natural product ,biology ,Drug discovery ,medicine.medical_treatment ,Active site ,Pharmacology ,medicine.disease_cause ,Baicalein ,chemistry.chemical_compound ,chemistry ,medicine ,biology.protein ,Mode of action ,Baicalin ,Coronavirus - Abstract
Human infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause coronavirus disease 19 (COVID-19) and there is currently no cure. The 3C-like protease (3CLpro), a highly conserved protease indispensable for replication of coronaviruses, is a promising target for development of broad-spectrum antiviral drugs. To advance the speed of drug discovery and development, we investigated the inhibition of SARS-CoV-2 3CLpro by natural products derived from Chinese traditional medicines. Baicalin and baicalein were identified as the first non-covalent, non-peptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography is distinctly different from those of known inhibitors. Baicalein is perfectly ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a “shield” in front of the catalytic dyad to prevent the peptide substrate approaching the active site. The simple chemical structure, unique mode of action, and potent antiviral activities in vitro, coupled with the favorable safety data from clinical trials, emphasize that baicalein provides a great opportunity for the development of critically needed anti-coronaviral drugs.
- Published
- 2020
88. Structural Basis for the Inhibition of the RNA-Dependent RNA Polymerase from SARS-CoV-2 by Remdesivir
- Author
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Yuan Chao Xie, Xiaodong Luan, Shuyang Zhang, Qingya Shen, Sheng-Ce Tao, Minqi Gao, Yan Zhang, Guanghui Tian, H. Eric Xu, Chunyou Mao, Wanchao Yin, Jingshan Shen, Xiaoxi Wang, He wei Jiang, Yechun Xu, Haixia Su, Dan-Dan Shen, Fulai Zhou, Yi Jiang, Wenfeng Zhao, Hualiang Jiang, and Shenghai Chang
- Subjects
Chemistry ,medicine.drug_class ,Base pair ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,RNA-dependent RNA polymerase ,RNA ,Virus diseases ,Virology ,chemistry.chemical_compound ,RNA polymerase ,medicine ,Viral rna ,Antiviral drug - Abstract
The pandemic of Corona Virus Disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global crisis. The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a direct target of the antiviral drug, Remdesivir. Here we report the structure of the SARS-CoV-2 RdRp either in the apo form or in complex with a 50-base template-primer RNA and Remdesivir at a resolution range of 2.5-2.8 Å. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is incorporated into the first replicated base pair and terminates the chain elongation. Our structures provide critical insights into the working mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.
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- 2020
89. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors
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Hong Liu, Haitao Yang, Fang Bai, Yinkai Duan, Zihe Rao, Xiuna Yang, Bing Zhang, Fengjiang Liu, Luke W. Guddat, Xing-Lou Yang, Zhenming Jin, Meiqin Liu, Lin Wang, Yechun Xu, Xiaoyu Du, Tian You, Ren-Di Jiang, Cheng-Feng Qin, Kailin Yang, Yong-Qiang Deng, Gengfu Xiao, Zhengli Shi, Yao Zhao, Leike Zhang, Xiang Liu, Xiaofeng Li, Liu X, Wenqing Xu, Jing Yu, Chao Peng, and Hualiang Jiang
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Drug ,0303 health sciences ,medicine.medical_specialty ,Protease ,Multidisciplinary ,business.industry ,Viral protein ,medicine.medical_treatment ,media_common.quotation_subject ,030303 biophysics ,Pharmacology ,medicine.disease ,medicine.disease_cause ,03 medical and health sciences ,Medical microbiology ,Viral replication ,Docking (molecular) ,Viral pneumonia ,medicine ,business ,030304 developmental biology ,media_common ,Coronavirus - Abstract
A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019–2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1–4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds—including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds—as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available. A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.
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- 2020
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90. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease
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Yao Zhao, Jian Li, Lei Ke Zhang, Xi Cheng, Wenhao Dai, Xiang Liu, Xiuna Yang, Jiang Wang, Xia Ming Jiang, Hualiang Jiang, Bing Zhang, Fengjiang Liu, Haitao Yang, Hong Liu, Shulei Hu, Xiaobo Cen, Yechun Xu, Haixia Su, Xiong Xie, Zihe Rao, Haofeng Wang, Jingjing Peng, Zhenming Jin, Fang Bai, Chunpu Li, You Li, and Gengfu Xiao
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medicine.drug_class ,Viral protein ,medicine.medical_treatment ,Pneumonia, Viral ,medicine.disease_cause ,Antiviral Agents ,03 medical and health sciences ,Betacoronavirus ,0302 clinical medicine ,In vivo ,Drug Discovery ,medicine ,Humans ,Pandemics ,Research Articles ,030304 developmental biology ,Coronavirus ,chemistry.chemical_classification ,0303 health sciences ,Protease ,Multidisciplinary ,SARS-CoV-2 ,R-Articles ,Biochem ,COVID-19 ,Virology ,Enzyme ,chemistry ,Viral replication ,030220 oncology & carcinogenesis ,Vero cell ,Antiviral drug ,Coronavirus Infections ,Research Article - Abstract
Promising antiviral protease inhibitors With no vaccine or proven effective drug against the virus that causes coronavirus disease 2019 (COVID-19), scientists are racing to find clinical antiviral treatments. A promising drug target is the viral main protease M pro , which plays a key role in viral replication and transcription. Dai et al. designed two inhibitors, 11a and 11b, based on analyzing the structure of the M pro active site. Both strongly inhibited the activity of M pro and showed good antiviral activity in cell culture. Compound 11a had better pharmacokinetic properties and low toxicity when tested in mice and dogs, suggesting that this compound is a promising drug candidate. Science , this issue p. 1331
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- 2020
91. Nelfinavir Is Active Against SARS-CoV-2 in Vero E6 Cells
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Weiliang Zhu, Xiangyun Lu, Jingshan Shen, Li Lanjuan, Nanping Wu, Yechun Xu, Zhijian Xu, and Yao Hangping
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Protease ,Chemistry ,Drug discovery ,medicine.medical_treatment ,virus diseases ,Pharmacology ,biochemical phenomena, metabolism, and nutrition ,Docking (dog) ,Nelfinavir ,immune system diseases ,Vero cell ,medicine ,Potency ,Nelfinavir mesylate ,medicine.drug ,EC50 - Abstract
Utilizing an integrative computational drug discovery approach, we predicted that nelfinavir is a potential inhibitor of SARS-CoV-2 main protease. Further docking nelfinavir to 30 potential target proteins of COVID-19, we found that nelfinavir is most probably a multi-target agent. The half-maximal effective concentration (EC50) of nelfinavir mesylate against SARS-CoV-2 was 2.89±0.65 μM while that of remdesivir was 1.00±0.34 μM, both drugs showed similar dose-response curves. Based on its high potency against SARS-CoV-2 at cellular level, its higher exposure in lung than in plasma, its good safe profile and its potential to reduce inflammation, nelfinavir deserves further exploration for the treatment of COVID-19.
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- 2020
92. Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease
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Haixia Su, Jian Li, Xi Cheng, Wenhao Dai, You Li, Haitao Yang, Xiuna Yang, Gengfu Xiao, Xiaming Jiang, Hong Liu, Jingjing Peng, Hualiang Jiang, Jiang Wang, Zhenming Jin, Fengjiang Liu, Haofeng Wang, Bing Zhang, Xiang Liu, Chunpu Li, Yechun Xu, Shulei Hu, Zihe Rao, Xiaobo Cen, Xiong Xie, Fang Bai, Yao Zhao, and Leike Zhang
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Drug ,chemistry.chemical_classification ,Protease ,genetic structures ,medicine.drug_class ,Peptidomimetic ,Chemistry ,media_common.quotation_subject ,medicine.medical_treatment ,behavioral disciplines and activities ,Enzyme ,Biochemistry ,Viral replication ,In vivo ,medicine ,Antiviral drug ,IC50 ,psychological phenomena and processes ,media_common - Abstract
SARS-CoV-2 is the etiological agent responsible for the COVID-19 outbreak in Wuhan. Specific antiviral drug are urgently needed to treat COVID-19 infections. The main protease (Mpro) of SARS-CoV-2 is a key CoV enzyme that plays a pivotal role in mediating viral replication and transcription, which makes it an attractive drug target. In an effort to rapidly discover lead compounds targeting Mpro, two compounds (11a and 11b) were designed and synthesized, both of which exhibited excellent inhibitory activity with an IC50 value of 0.05 μM and 0.04 μM respectively. Significantly, both compounds exhibited potent anti-SARS-CoV-2 infection activity in a cell-based assay with an EC50 value of 0.42 μM and 0.33 μM, respectively. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a and 11b were determined at 1.5 Å resolution, respectively. The crystal structures showed that 11a and 11b are covalent inhibitors, the aldehyde groups of which are bound covalently to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity which is promising drug leads with clinical potential that merits further studies.
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- 2020
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93. Structure of Mpro from COVID-19 virus and discovery of its inhibitors
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Meiqin Liu, Cheng-Feng Qin, Luke W. Guddat, Xiaoyu Du, Ren-Di Jiang, Xiaofeng Li, Fang Bai, Fengjiang Liu, Jing Yu, Xiuna Yang, Yechun Xu, Wenqing Xu, Bing Zhang, Chao Peng, Liu X, Lin Wang, Hong Liu, Kailin Yang, Zihe Rao, Tian You, Zhenming Jin, Yong-Qiang Deng, Gengfu Xiao, Hualiang Jiang, Yao Zhao, Leike Zhang, Xiang Liu, Haitao Yang, Xing-Lou Yang, Zhengli Shi, and Yinkai Duan
- Subjects
Drug ,Virtual screening ,Protease ,business.industry ,medicine.medical_treatment ,High-throughput screening ,media_common.quotation_subject ,Computational biology ,medicine.disease ,medicine.disease_cause ,Clinical trial ,Viral replication ,Viral pneumonia ,medicine ,business ,Coronavirus ,media_common - Abstract
SUMMARYA new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1–4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mprois a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mproin complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mprowith IC50values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.
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- 2020
- Full Text
- View/download PDF
94. Diterpenoids from the Root Bark of
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Yifan, Fu, Xiaoyu, Ding, Xianglei, Zhang, Xingcheng, Shao, Jihui, Zhao, Yechun, Xu, Xiaomin, Luo, and Weimin, Zhao
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Molecular Docking Simulation ,Phosphoric Diester Hydrolases ,Cell Line, Tumor ,Plant Bark ,Humans ,Diterpenes ,Pinus - Abstract
Thirty-two diterpenoids were obtained from the root bark of
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- 2020
95. Complete Chloroplast Genomes of Three Medicinal Alpinia Species: Genome Organization, Comparative Analyses and Phylogenetic Relationships in Family Zingiberaceae
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Yuan-Jun Ye, Jin-Mei Liu, Dong-Mei Li, Gen-Fa Zhu, and Yechun Xu
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0106 biological sciences ,0301 basic medicine ,comparative analysis ,Alpinia oxyphylla ,Alpinia katsumadai ,Plant Science ,01 natural sciences ,Genome ,Amomum ,Article ,03 medical and health sciences ,single nucleotide polymorphisms ,Phylogenetics ,lcsh:Botany ,Alpinia pumila ,Alpinia zerumbet ,Indel ,Ecology, Evolution, Behavior and Systematics ,Genomic organization ,Genetics ,Ecology ,biology ,Phylogenetic tree ,phylogenetic relationship ,Alpinia ,biology.organism_classification ,lcsh:QK1-989 ,030104 developmental biology ,indels ,chloroplast genome ,010606 plant biology & botany - Abstract
Alpinia katsumadai (A. katsumadai), Alpinia oxyphylla (A. oxyphylla) and Alpinia pumila (A. pumila), which belong to the family Zingiberaceae, exhibit multiple medicinal properties. The chloroplast genome of a non-model plant provides valuable information for species identification and phylogenetic analysis. Here, we sequenced three complete chloroplast genomes of A. katsumadai, A. oxyphylla sampled from Guangdong and A. pumila, and analyzed the published chloroplast genomes of Alpinia zerumbet (A. zerumbet) and A. oxyphylla sampled from Hainan to retrieve useful chloroplast molecular resources for Alpinia. The five Alpinia chloroplast genomes possessed typical quadripartite structures comprising of a large single copy (LSC, 87,248&ndash, 87,667 bp), a small single copy (SSC, 15,306&ndash, 18,295 bp) and a pair of inverted repeats (IR, 26,917&ndash, 29,707 bp). They had similar gene contents, gene orders and GC contents, but were slightly different in the numbers of small sequence repeats (SSRs) and long repeats. Interestingly, fifteen highly divergent regions (rpl36, ycf1, rps15, rpl22, infA, psbT-psbN, accD-psaI, petD-rpoA, psaC-ndhE, ccsA-ndhD, ndhF-rpl32, rps11-rpl36, infA-rps8, psbC-psbZ, and rpl32-ccsA), which could be suitable for species identification and phylogenetic studies, were detected in the Alpinia chloroplast genomes. Comparative analyses among the five chloroplast genomes indicated that 1891 mutational events, including 304 single nucleotide polymorphisms (SNPs) and 118 insertion/deletions (indels) between A. pumila and A. katsumadai, 367 SNPs and 122 indels between A. pumila and A. oxyphylla sampled from Guangdong, 331 SNPs and 115 indels between A. pumila and A. zerumbet, 371 SNPs and 120 indels between A. pumila and A. oxyphylla sampled from Hainan, and 20 SNPs and 23 indels between the two accessions of A. oxyphylla, were accurately located. Additionally, phylogenetic relationships based on SNP matrix among 28 whole chloroplast genomes showed that Alpinia was a sister branch to Amomum in the family Zingiberaceae, and that the five Alpinia accessions were divided into three groups, one including A. pumila, another including A. zerumbet and A. katsumadai, and the other including two accessions of A. oxyphylla. In conclusion, the complete chloroplast genomes of the three medicinal Alpinia species in this study provided valuable genomic resources for further phylogeny and species identification in the family Zingiberaceae.
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- 2020
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96. Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase
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Dang Wu, sisi lu, Weiqiang Lu, shuyin ze, Yechun Xu, Jiacheng He, Jin Huang, Qian Hu, Wanyan Wang, Wuyan Chen, Ying Huang, and Zehui Liu
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0301 basic medicine ,Models, Molecular ,Oxidoreductases Acting on CH-CH Group Donors ,Encephalomyelitis, Autoimmune, Experimental ,Polyunsaturated Alkamides ,Encephalomyelitis ,T cell ,Dihydroorotate Dehydrogenase ,Pharmacology ,Crystallography, X-Ray ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Myelin ,Jurkat Cells ,0302 clinical medicine ,Alkaloids ,Piperidines ,medicine ,Animals ,Humans ,Benzodioxoles ,Molecular Targeted Therapy ,Enzyme Inhibitors ,IC50 ,Myelin Sheath ,Biological Products ,Multiple sclerosis ,medicine.disease ,Mixed lymphocyte reaction ,Peptide Fragments ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Piperine ,Dihydroorotate dehydrogenase ,Female ,Myelin-Oligodendrocyte Glycoprotein ,Spleen - Abstract
Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC50 value of 0.88 μM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 A resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a useful model for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood–brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel role for piperine in the treatment of MS.
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- 2020
97. DC591017, a phosphodiesterase-4 (PDE4) inhibitor with robust anti-inflammation through regulating PKA-CREB signaling
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Heng Li, Rui Zhang, Yu Zhou, Hong Liu, Yechun Xu, Chunlan Feng, Xianglei Zhang, Fenghua Zhu, Xiaoqian Yang, Chen Fan, Wei Tang, and Jian Li
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0301 basic medicine ,Male ,Anti-Inflammatory Agents ,Inflammation ,Pharmacology ,CREB ,Biochemistry ,Proinflammatory cytokine ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,In vivo ,medicine ,Animals ,Humans ,Psoriasis ,Cyclic AMP Response Element-Binding Protein ,Cells, Cultured ,Gene knockdown ,Mice, Inbred BALB C ,Forskolin ,Imiquimod ,biology ,Molecular Structure ,Cyclic AMP-Dependent Protein Kinases ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Mice, Inbred C57BL ,030104 developmental biology ,RAW 264.7 Cells ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Phosphodiesterase 4 Inhibitors ,Signal transduction ,medicine.symptom ,Signal Transduction - Abstract
Phosphodiesterase-4 (PDE4) functions as a critical intracellular enzyme in immune cells and keratinocytes through the hydrolysis of cAMP. Inhibition of PDE4 has been considered as an effective therapeutic strategy in multiple inflammatory diseases. This study was intended to assess the anti-inflammatory effects of the PDE4 inhibitor, DC591017, both in vitro and in vivo. Murine RAW264.7 cells, BMDMs, BMDCs, and human NHEKs were incubated with DC591017 and then inflammatory mediators, intracellular cAMP and cAMP-mediated signaling pathways were analyzed. Carrageenan-induced acute inflammation in murine air pouches and rat paws, as well as imiquimod (IMQ)-induced psoriasis-like skin lesions were conducted to explore the therapeutic effects and underlying mechanisms of DC591017. We demonstrated herein that DC591017 suppressed the inflammatory responses of macrophages and DCs through promoting cAMP-dependent PKA-CREB signaling. Addition of forskolin functioned synergistically with DC591017, which could be blocked following H89 intervention or knockdown of PKA expression by siRNA transfection. In vivo, DC591017 treatment alleviated the leukocytes infiltration and secretion of inflammatory cytokines in murine air pouches and significantly attenuated carrageenan-induced paw swelling in rats. Moreover, we also illustrated that topical application of DC591017 ointment ameliorated IMQ-caused experimental psoriatic skin lesions, as evidenced by decreasing epidermal thickening and inflammatory infiltrations to inflamed skins. Consistently, DC591017 decreased expression of PDE4 isoforms and subsequently regulated PKA-CREB and NF-κB signaling. In brief, our study brought out a patent PDE4 inhibitor with robust anti-inflammation and provided the credible evidence in the treatment of patients with psoriasis.
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- 2020
98. Structure of M
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Zhenming, Jin, Xiaoyu, Du, Yechun, Xu, Yongqiang, Deng, Meiqin, Liu, Yao, Zhao, Bing, Zhang, Xiaofeng, Li, Leike, Zhang, Chao, Peng, Yinkai, Duan, Jing, Yu, Lin, Wang, Kailin, Yang, Fengjiang, Liu, Rendi, Jiang, Xinglou, Yang, Tian, You, Xiaoce, Liu, Xiuna, Yang, Fang, Bai, Hong, Liu, Xiang, Liu, Luke W, Guddat, Wenqing, Xu, Gengfu, Xiao, Chengfeng, Qin, Zhengli, Shi, Hualiang, Jiang, Zihe, Rao, and Haitao, Yang
- Subjects
Models, Molecular ,SARS-CoV-2 ,Pneumonia, Viral ,Drug Evaluation, Preclinical ,COVID-19 ,Viral Nonstructural Proteins ,Antiviral Agents ,Protein Structure, Tertiary ,Betacoronavirus ,Cysteine Endopeptidases ,Drug Design ,Drug Discovery ,Humans ,Protease Inhibitors ,Coronavirus Infections ,Pandemics ,Cells, Cultured ,Coronavirus 3C Proteases - Abstract
A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)
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- 2020
99. USP28 and USP25 are downregulated by Vismodegib in vitro and in colorectal cancer cell lines
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Yechun Xu, Hu Zhou, Li Shi, Lei Gu, Hui Wang, Mengying Zhu, Naixia Zhang, Yuanyuan Yang, Yiluan Ding, Qian Meng, Muya Xiong, and Haixia Su
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0301 basic medicine ,Thermal shift assay ,Cell Survival ,Pyridines ,Vismodegib ,Down-Regulation ,medicine.disease_cause ,Biochemistry ,Deubiquitinating enzyme ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Cell Line, Tumor ,medicine ,Humans ,Basal cell carcinoma ,Anilides ,Hedgehog Proteins ,Molecular Biology ,chemistry.chemical_classification ,biology ,Molecular Structure ,Cell Biology ,medicine.disease ,HCT116 Cells ,Hedgehog signaling pathway ,In vitro ,Molecular Docking Simulation ,030104 developmental biology ,Enzyme ,chemistry ,Carcinoma, Basal Cell ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Biocatalysis ,Carcinogenesis ,Colorectal Neoplasms ,Ubiquitin Thiolesterase ,medicine.drug ,Protein Binding ,Signal Transduction - Abstract
Deubiquitinase USP28 plays a crucial role in tumorigenesis by enhancing the stabilities of multiple cancer-related proteins including c-Myc, Notch1, and LSD1, and has become an attractive target for anticancer drug development. However, to date, only a few of USP28-targeted active compounds have been developed, and the active compound-binding pocket in USP28 has not been experimentally revealed yet. In this study, bioassay-based high-throughput screening was applied to discover USP28-targeted inhibitors from the commercially available drug library. Vismodegib, an inhibitor of Hedgehog signaling pathway and FDA-approved drug for the treatment of basal cell carcinoma, was found to exhibit inhibition activity against USP28 (IC50 : 4.41 ± 1.08 μm). Multiple biophysical and biochemical techniques including NMR, ITC, thermal shift assay, HDX-MS, and site-directed mutagenesis analysis were then used to characterize the interaction between Vismodegib and USP28. The binding pocket in USP28 for Vismodegib, which is mainly composed of two helical structures spanning D255-N278 and N286-Y293, was revealed. According to the possible binding pose generated by HDX-MS data-defined molecular docking, the binding cavity occupied by Vismodegib in USP28 aligns well with one of the reported-binding pockets in USP7 for its inhibitors. Furthermore, cellular assays were conducted to confirm that Vismodegib could interact with the evolutionarily related deubiquitinases USP28 and USP25 and downregulate the levels of the two enzymes' substrate proteins c-Myc, Notch1, and Tankyrase-1/2.
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- 2020
100. The use of widely targeted metabolomics profiling to quantify differences in medicinally important compounds from five Curcuma (Zingiberaceae) species
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Wei Li, Zhiqiang Wu, Jin-Mei Liu, Luke R. Tembrock, Xiao‐Ni Zhang, Jianjun Tan, Gen-Fa Zhu, Xueqing Chen, Yechun Xu, and Yuanjun Ye
- Subjects
Caesia ,biology ,Traditional medicine ,Pathway enrichment ,biology.organism_classification ,chemistry.chemical_compound ,Metabolomics ,chemistry ,Phytochemical ,Curcumin ,Zingiberaceae ,Curcuma ,Agronomy and Crop Science ,Targeted metabolomics - Abstract
The genus Curcuma is widely recognized for its diversity of medicinal and culinary uses yet metabolomic differences among Curcuma species are largely unknown, due to the lack of broadly targeted analytical studies. Here, Ultra-Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS) analysis was employed to interrogate the metabolomes of five Curcuma species which are commonly used in Chinese herbal medicine (C. aromatica, C. elata, C. longa, C. caesia and C. phaeocaulis). By processing these results through a pathway enrichment analysis, 432 metabolites (some associated with the curcumin pathway) were identified that varied by species. The quantity of curcuminoids in C. longa were found to be higher than that in the other four Curcuma species analyzed in this study. In addition, C. longa was found to have a greater diversity of phenolic acids, amino acid derivatives, and flavonoids associated with the curcumin biosynthesis pathway. However, medicinal compounds such as 6-gingerol were found in lower quantities in C. longa compared to all other species in this study. This study provides new insights into Curcuma phytochemical pathways and allows for the development of functional foods tailored to specific needs from these species.
- Published
- 2022
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