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A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2228-2246页

作者： Jiangtao Fu Pingping Zhang Zhiguo Sun Guodong Lu Qi Cao Yiting Chen Wenbin Wu Jiabao Zhang Chunlin Zhuang chunquan sheng Jiajun Xu Ying Lu Pei Wang The Center for Basic Research and Innovation of Medicine and Pharmacy(MOE) School of PharmacyNaval Medical UniversityShanghai 200433China National Demonstration Center for Experimental Pharmaceutical Education Naval Medical University/Second Military Medical UniversityShanghai 200433China Department of Diving and Hyperbaric Medicine Naval Special Medical CenterNaval Medical UniversityShanghai 200433China

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)***,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major ***,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of *** oxide(NO)is a versatile biological molecule that can degrade extracellular *** this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH *** with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ***@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota *** findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

关键词： Nonalcoholic steatohepatitis Nanotherapy Farnesoid X receptor Ferroptosis Fibrosis Obeticholic acid S-Nitrosothiol Liproxstatin-1

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靶向蛋白降解技术的开发之路

海军军医大学学报 2024年第6期45卷 671-679页

作者：王蔚盛春泉海军军医大学(第二军医大学)药学系药物化学教研室

靶向蛋白降解是当前热门的化学敲除工具和新药研发策略。与传统小分子抑制剂相比，靶向蛋白降解技术利用机体固有的蛋白清除机制(如泛素-蛋白酶体系统或溶酶体途径)特异性降解致病目标蛋白，在降低药物毒性和不良反应、克服耐药及靶向... 详细信息

靶向蛋白降解是当前热门的化学敲除工具和新药研发策略。与传统小分子抑制剂相比，靶向蛋白降解技术利用机体固有的蛋白清除机制(如泛素-蛋白酶体系统或溶酶体途径)特异性降解致病目标蛋白，在降低药物毒性和不良反应、克服耐药及靶向“难成药”靶点等方面具有突出优势。本文结合笔者团队的相关研究，聚焦多种新兴的靶向蛋白降解技术，如蛋白水解靶向嵌合体、分子胶、溶酶体靶向嵌合体、自噬体绑定化合物、自噬靶向嵌合体等，分析靶向蛋白降解技术的应用前景和未来发展趋势。

关键词：靶向蛋白降解泛素-蛋白酶体系统溶酶体途径蛋白水解靶向嵌合体新药研发

Targeting necroptosis in anticancer therapy:mechanisms and modulators

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Acta Pharmaceutica Sinica B 2020年第9期10卷 1601-1618页

作者： Ying Wu Guoqiang Dong chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

Necroptosis,a genetically programmed form of necrotic cell death,serves as an important pathway in human *** a critical cell-killing mechanism,necroptosis is associated with cancer progression,metastasis,and *** necroptosis pathway by small molecule modulators is emerging as an effective approach in cancer therapy,which has the advantage to bypass the apoptosis-resistance and maintain antitumor ***,a better understanding of the mechanism of necroptosis and necroptosis modulators is necessary to develop novel strategies for cancer *** review will summarize recent progress of the mechanisms and detecting methods of *** particular,the relationship between necroptosis and cancer therapy and medicinal chemistry of necroptosis modulators will be focused on.

关键词： Cell death Necroptosis Inducers Inhibitors Anticancer therapy

Structural simplification: an efficient strategy in lead optimization

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Acta Pharmaceutica Sinica B 2019年第5期9卷 880-901页

作者： shengzheng Wang Guoqiang Dong chunquan sheng Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai200433China Department of Medicinal Chemistry and Pharmaceutical Analysis School of PharmacyFourth Military MedicalUniversityXi’an710032China

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding 'molecular obesity'. The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

关键词： Structural simplification Lead optimization Drug discovery Drug design Reducing rings number Reducing chiral centers Structure-based simplification Pharmacophore-based simplification

Small molecules for combating multidrug-resistant superbug Candida auris infections

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4056-4074页

作者： Jie Tu Na Liu Yahui Huang Wanzhen Yang chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China

Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.

关键词： Candidaauris Antifungal agents Drug resistance Virulence factors Antifungal targets

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靶向难成药蛋白——蛋白质降解剂的力量

Science Bulletin 2024年第11期69卷 1776-1797页

作者：张超刘永波李广晨杨周立韩驰孙秀云盛春泉丁克饶燏 State Key Laboratory of Molecular Oncology MOE Key Laboratory of Protein SciencesMOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical BiologySchool of Pharmaceutical SciencesTsinghua UniversityBeijing 100084China Changping Laboratory Beijing 102206China School of Pharmacy Second Military Medical UniversityShanghai 200433China State Key Laboratory of Chemical Biology Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical *** to statistics,over 80%of disease-related pathogenic proteins cannot be targeted by current conventional treatment *** recent years,with the advancement of basic research and new technologies,the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug *** them,targeted protein degradation technology is a breakthrough drug development strategy for challenging drug *** technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within *** new form of drug development includes various types such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting Chimaera(LYTAC),autophagosometethering compound(ATTEC),autophagy-targeting chimera(AUTAC),autophagy-targeting chimera(AUTOTAC),degrader-antibody conjugate(DAC).This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug ***,the article looks forward to the future development direction and application prospects of targeted protein degradation technology.

关键词： Undruggables Targeted protein degradation PROTAC Molecule glue DAC LYTAC

Evodiamine-inspired dual inhibitors of histone deacetylase 1(HDAC1) and topoisomerase 2(TOP2) with potent antitumor activity

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Acta Pharmaceutica Sinica B 2020年第7期10卷 1294-1308页

作者： Yahui Huang Shuqiang Chen Shanchao Wu Guoqiang Dong chunquan sheng Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug *** by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1(HDAC1)and topoisomerase 2(TOP2)dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor ***,compound 30 a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model(TGI=75.2%,150 mg/kg,p.o.)without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their *** together,this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

关键词： Evodiamine Histone deacetylase Topoisomerase Dual inhibitors Antitumor activity

Constructing virtual combinatorial fragment libraries based upon MDL Drug Data Report database

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Science China Chemistry 2007年第3期50卷 364-371页

作者： ZHANG Min sheng chunquan XU Hui SONG YunLong ZHANG WanNian School of Pharmacy Second Military Medical UniversityShanghai 200433China

Structural analysis of known drugs or drug-like compounds provides important information for drug design. The 142553 drug molecules in the MDL Drug Data Report database were analyzed, and then the common structural features were extracted. According to the common structural features, drug molecules were segmented into 32017 fragments, including 13642 ring fragments, 10076 linker fragments, and 8299 side chain fragments. These fragments were further used to establish three types of virtual combinatorial fragment libraries: a basic framework library containing 13574 rings; a linker library of 8051 linkers and a pharmacophore library of 34244 fragments combined by rings and side chains. After energy minimization, all fragments in the above three libraries maintain reasonable geometrical features and spatial conformations, and would be useful for building a virtual combinatorial database and de novo drug design.

关键词： drug design fragment molecular database statistical analysis drug molecule

NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2859-2868页

作者： Ying Wu Congying Pu Yixian Fu Guoqiang Dong Min Huang chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 201203China

Nicotinamide phosphoribosyl transferase(NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and ***,therapeutic benefit of NAMPT enzymatic inhibitors appears very limited,likely due to the failure to intervene nonenzymatic functions of ***,we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells(MDSCs) via a mechanism independent of its enzymatic *** proteolysis-targeting chimera(PROTAC) technology,PROTAC A7 is identified as a potent and selective degrader of NAMPT,which degrades intracellular NAMPT(iNAMPT) via the ubiquitin-proteasome system,and in turn decreases the secretion of extracellular NAMPT(eNAMPT),the major player of the non-enzymatic activity of *** vivo,PROTAC A7 efficiently degrades NAMPT,inhibits tumor infiltrating MDSCs,and boosts antitumor *** note,the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on ***,our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment,and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT,pointing out a new direction for the development of NAMPT-targeted therapies.

关键词： NAMPT Non-enzymatic function eNAMPT Cancer MDSC PROTAC Tumor immunity Immunotherapy