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Discovery and characterization of naturally occurring covalent inhibitors of SARS-CoV-2 M~(pro)from the antiviral herb Ephedra

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Chinese Journal of Natural Medicines 2024年第9期22卷 797-807页

作者： HU Qing ZHANG Yiwen CHEN Pengcheng ZHANG Yani ZHU Guanghao LIU Wei WANG Chaoran ZHENG Shuilian SHEN Nonger WANG Haonan HUANG Ping ge guangbo Center for Clinical Pharmacy Cancer CenterDepartment of PharmacyZhejiang Provincial People’s Hospital(Affiliated People’s Hospital)Hangzhou Medical CollegeHangzhou 310014China Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai 201203China Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Shanghai 200021China Dalian Institute of Chemical Physics Chinese Academy of SciencesDalian 116023China

The Chinese herb Ephedra(also known as Mahuang)has been extensively utilized for the prevention and treatment of coronavirus-induced diseases,including coronavirus disease 2019(COVID-19).However,the specific anti-SARS-CoV-2 compounds and mechanisms have not been fully *** main protease(M~(pro))of SARS-CoV-2 is a highly conserved enzyme responsible for proteolytic processing during the viral life cycle,making it a critical target for the development of antiviral *** study aimed to identify naturally occurring covalent inhibitors of SARS-CoV-2 M~(pro)from Ephedra and to investigate their covalent binding *** results demonstrated that the non-alkaloid fraction of Ephedra(ENA)exhibited a potent inhibitory effect against the SARS-CoV-2 M~(pro)effect,whereas the alkaloid fraction did ***,the chemical constituents in ENA were identified,and the major constituents'anti-SARS-CoV-2 M~(pro)effects were *** the tested constituents,herbacetin(HE)and gallic acid(GA)were found to inhibit SARS-CoV-2 M~(pro)in a time-and dose-dependent *** combination displayed a significant synergistic effect on this key ***,various techniques,including inhibition kinetic assays,chemoproteomic methods,and molecular dynamics simulations,were employed to further elucidate the synergistic anti-M~(pro)mechanisms of the combination of HE and ***,this study deciphers the naturally occurring covalent inhibitors of SARS-CoV-2 M~(pro)from Ephedra and characterizes their synergistic anti-M~(pro)synergistic effect,providing robust evidence to support the anti-coronavirus efficacy of Ephedra.

关键词： Main protease Ephedra Ephedra non-alkaloid fraction Covalent inhibitors Synergistic effect

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Discovery and characterization of naturally occurring covalent inhibitors of SARS-CoV-2 Mpro from the antiviral herb Ephedra

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Chinese Journal of Natural Medicines 2024年第9期 797-807页

作者： HU Qing ZHANG Yiwen CHEN Pengcheng ZHANG Yani ZHU Guanghao LIU Wei WANG Chaoran ZHENG Shuilian SHEN Nonger WANG Haonan HUANG Ping ge guangbo Center for Clinical Pharmacy Cancer Center Department of Pharmacy Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese Medicine Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine Dalian Institute of Chemical Physics Chinese Academy of Sciences

The Chinese herb Ephedra（also known as Mahuang） has been extensively utilized for the prevention and treatment of coronavirus-induced diseases, including coronavirus disease 2019（COVID-19）. However, the specific anti-SARS-CoV-2 compounds and mechanisms have not been fully elucidated. The main protease(Mpro) of SARS-CoV-2 is a highly conserved enzyme responsible for proteolytic processing during the viral life cycle, making it a critical target for the development of antiviral therapies. This study aimed to identify naturally occurring covalent inhibitors of SARS-CoV-2 Mprofrom Ephedra and to investigate their covalent binding sites. The results demonstrated that the non-alkaloid fraction of Ephedra（ENA） exhibited a potent inhibitory effect against the SARS-CoV-2 Mproeffect, whereas the alkaloid fraction did not. Subsequently, the chemical constituents in ENA were identified, and the major constituents' anti-SARS-CoV-2 Mproeffects were evaluated. Among the tested constituents, herbacetin（HE） and gallic acid（GA）were found to inhibit SARS-CoV-2 Mproin a time-and dose-dependent manner. Their combination displayed a significant synergistic effect on this key enzyme. Additionally, various techniques, including inhibition kinetic assays, chemoproteomic methods, and molecular dynamics simulations, were employed to further elucidate the synergistic anti-Mpromechanisms of the combination of HE and GA. Overall, this study deciphers the naturally occurring covalent inhibitors of SARS-CoV-2 Mprofrom Ephedra and characterizes their synergistic anti-Mprosynergistic effect, providing robust evidence to support the anti-coronavirus efficacy of Ephedra.

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Preface for special issue on new analytical techniques and methods in drug metabolism and pharmacokinetics

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Journal of Pharmaceutical Analysis 2020年第3期10卷 I0001-I0002页

作者： guangbo ge Mingshe Zhu Institute of Interdisciplinary Integrative Medicine Research.Shanghai University of Traditional Chinese Medicine ShanghaiChina MassDefect Technologies Princeton.NJ.USA.

Analytical technologies and approaches for drug metabolism and pharmacokinetics(DMPK)research in the pharmaceutical industry and academic research institutes have evolved rapidly over the past *** one hand,the discovery and development of small molecule drug candidates requires earlier and better understanding of their absorption,distribution,metabolism and excretion(ADME)in human as well as their interactions with metabolizing enzymes.

关键词： metabolism pharmacokinetics drug

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Recent progress and challenges in screening and characterization of UGT1A1 inhibitors

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Acta Pharmaceutica Sinica B 2019年第2期9卷 258-278页

作者： Xia Lv Yangliu Xia Moshe Finel Jingjing Wu guangbo ge Ling Yang Institute of Interdisciplinary Medicine Shanghai University of Traditional Chinese Medicine Key Laboratory of Biotechnology and Bioresources Utilization Ministry of Education College of Life ScienceDalian Minzu University Dalian Institute of Chemical Physics Chinese Academy of Sciences Division of Pharmaceutical Chemistry and Technology Faculty of Pharmacy University of Helsinki

Uridine-diphosphate glucuronosyltransferase 1 A1(UGT1 A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1 A1 may trigger adverse drug/herb–drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration(FDA)and the European Medicines Agency(EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1 A1 prior to approval. This review focuses on the significance,progress and challenges in discovery and characterization of UGT1 A1 inhibitors. Recent advances in the development of UGT1 A1 probes and their application for screening UGT1 A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1 A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1 A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1 A1 inhibitors and for facilitating investigations on UGT1 A1–ligand interactions.

关键词： UGT1A1 inhibitors Drug/herbdrug interactions Probe substrates High-throughput screening

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Human carboxylesterases:a comprehensive review

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Acta Pharmaceutica Sinica B 2018年第5期8卷 699-712页

作者： Dandan Wang Liwei Zou Qiang Jin Jie Hou guangbo ge Ling Yang Institute of Interdisciplinary Medicine Shanghai University of Traditional Chinese Medicine Dalian Medical University

Mammalian carboxylesterases(CEs) are key enzymes from the serine hydrolase *** the human body, two predominant carboxylesterases(CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.

关键词： Human carboxylesterases CES1 CES2 Substrate preference Inhibitor spectra Inducer

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Sustainable utilization of precious Chinese medicines:challenges and the road ahead

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Chinese Journal of Natural Medicines 2022年第11期20卷 801-804页

作者： GONG Jiahao LI Haiying XU Jianguang CHEN Hongzhuan ge guangbo Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai 201203China

Traditional Chinese medicine(TCM)is considered as a unique treasure of Chinese civilization for its profound theoretical system and extensive experience in clinical practice for more than two thousand *** one of the most commonly used folk medicines,Chinese medicines have made indelible contributions to well-being maintenance and disease treatment,as well as the progress of human civilization[1].

关键词： medicines civilization ahead

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Synthesis and Biological Evaluation of Hydroxylcoumarin Derivatives as Antioxidant Agents

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Chemical Research in Chinese Universities 2017年第2期33卷 194-199页

作者： CHEN Chen WANG Ping ZOU Liwei YANG Ling FAN Yiming HU Wenzhong ge guangbo College of Life Science Dalian Minzu University Dalian 116600 P. R. China Laboratory of PharmaceuticaI Resource Discovery Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 R R. China

In this study, esculetin（1） was chosen as a lead compound and some structural modifications weredesigned to explore the antioxidant activities of esculetin derivatives. Meanwhile, a convenient method for selectivemethylation of catechol cournarins with different bases was developed. Furthermore, a few 5,7-dihydroxylcoumarinswere synthesized and 7-hydroxylcoumarins were employed in order to explore the potential structure-antioxidantactivity relationships. The antioxidant activities of these compounds were evaluated and compared with standardantioxidant Trolox by the 22＇-diphenyl-l-picrylhydrazyl（DPPH） assay, 2,2＇-azinobis-（3-ethylbenzthiazoline-6-sulfonate）cation（ABTS＋） assay and ferric reducing antioxidant power（FRAP） assay. The results show that the catechol group isthe key pharmacophore. Meanwhile, introducing electronegative groups at the C4 position of esculetin（1） mayenhance the antioxidative capacity, while introducing a group containing nitrogen as a hydrogen bond acceptor at theC8 position may slightly reduce the antioxidative capacity, Among them, the most powerful antioxidants are com-pounds 5 and 7, which exhibit higher antioxidant activity than esculetin（1） in all assays.

关键词： Hydroxylcoumarm Antioxidant activity Radical scavenging effect Structure-activity relationship

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Optical substrates for drug-metabolizing enzymes: Recent advances and future perspectives

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1068-1099页

作者： Qiang Jin Jing Jing Wu Yue Wu Hongxin Li Moshe Finel Dandan Wang guangbo ge Shanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine ResearchShanghai University of Traditional Chinese MedicineShanghai 201203China Department of Clinical Pharmacology College of PharmacyDalian Medical UniversityDalian 116044China Division of Pharmaceutical Chemistry and Technology Faculty of PharmacyUniversity of HelsinkiHelsinki 00014Finland

Drug-metabolizing enzymes(DMEs),a diverse group of enzymes responsible for the metabolic elimination of drugs and other xenobiotics,have been recognized as the critical determinants to drug safety and *** and understanding the key roles of individual DMEs in drug metabolism and toxicity,as well as characterizing the interactions of central DMEs with xenobiotics require reliable,practical and highly specific tools for sensing the activities of these enzymes in biological *** the last few decades,the scientists have developed a variety of optical substrates for sensing human DMEs,parts of them have been successfully used for studying target enzyme(s)in tissue preparations and living ***,molecular design principals and recent advances in the development and applications of optical substrates for human DMEs have been reviewed ***,the challenges and future perspectives in this field are also *** presented information offers a group of practical approaches and imaging tools for sensing DMEs activities in complex biological systems,which strongly facilitates high-throughput screening the modulators of target DMEs and studies on drug/herb-drug interactions,as well as promotes the fundamental researches for exploring the relevance of DMEs to human diseases and drug treatment outcomes.

关键词： Optical substrates Drug-metabolizing enzymes(DMEs) Fluorescence-based assay High-throughput screening

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An Expedient Method for Regioselective Methylation of Catechol Coumarins

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Chemical Research in Chinese Universities 2016年第5期32卷 786-791页

作者： LU Junxia WANG Ping HOU Jie ZOU Liwei CUI Pan YANG Ling ge guangbo GONG Xiaojie College of Environmental and Chemical Engineering Dalian University Dalian 116622 P. R. China College of Medical Dalian University Dalian 116622 P. R. China Laboratory of Pharmaceutical Resource Discovery Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 P. R. China College of Basic Medical Sciences Dalian Medical University Dalian 116044 P. R. China

An expedient and efficient method for selective methylation of catechol coumarins by working with different alkalis under appropriate reaction conditions was reported. Esculetins were selectively methylated at position 6 and position 7 in good yields using CH3I in the presence of Nail and Na2CO3, respectively. However, daphnetins showed less regioselectivity under the same reaction conditions. Furthermore, the site preference for the methylation reaction was interpreted by the density functional theory at B3LYP/6-31 ＋G（d） level.

关键词： Catechol coumarin Regioselective methylation Density functional theory

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Comparison of the inhibition potentials of icotinib and erlotinib against human UDP-glucuronosyltransferase 1A1

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Acta Pharmaceutica Sinica B 2017年第6期7卷 657-664页

作者： Xuewei Cheng Xia Lv Hengyan Qu Dandan Li Mengmeng Hu Wenzhi Guo guangbo ge Ruihua Dong Clinical Pharmacology Laboratory Military Academy of Medical Science Hospital Dalian Institute of Chemical Physics Chinese Academy of Sciences College of Life Science Dalian Nationalities University Department of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital of Zhengzhou University Institute of Interdisciplinary Medicine Shanghai University of Traditional Medicine

UDP-glucuronosyltransferase 1A1(UGT1A1) plays a key role in detoxification of many potentially harmful compounds and drugs. UGT1A1 inhibition may bring risks of drug–drug interactions(DDIs), hyperbilirubinemia and drug-induced liver injury. This study aimed to investigate and compare the inhibitory effects of icotinib and erlotinib against UGT1A1, as well as to evaluate their potential DDI risks via UGT1A1 inhibition. The results demonstrated that both icotinib and erlotinib are UGT1A1 inhibitors, but the inhibitory effect of icotinib on UGT1A1 is weaker than that of erlotinib. The IC_(50) values of icotinib and erlotinib against UGT1A1-mediated NCHN-O-glucuronidation in human liver microsomes(HLMs) were 5.15 and 0.68 μmol/L, respectively. Inhibition kinetic analyses demonstrated that both icotinib and erlotinib were non-competitive inhibitors against UGT1A1-mediated glucuronidation of NCHN in HLMs, with the Kivalues of 8.55 and 1.23 μmol/L, respectively. Furthermore, their potential DDI risks via UGT1A1 inhibition were quantitatively predicted by the ratio of the areas under the concentration–time curve(AUC) of NCHN. These findings are helpful for the medicinal chemists todesign and develop next generation tyrosine kinase inhibitors with improved safety, as well as to guide reasonable applications of icotinib and erlotinib in clinic, especially for avoiding their potential DDI risks via UGT1A1 inhibition.

关键词： Icotinib Erlotinib UGT1A1 Inhibitory effects Drug–drug interactions(DDIs)

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