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Science China Chemistry 2024年第2期67卷 568-575页

作者： Jiasheng Qian Li-Cai Liu Zhi-Hao Chen Yuan Liu Yin Li Qingjiang Li Honggen Wang Guangdong Key Laboratory of Chiral Molecule and drug discovery School of Pharmaceutical SciencesSun Yat-Sen UniversityGuangzhou510006China

α-Functionalized organoborons are useful building blocks and key structural elements in functional molecules.Their previous synthesis relied on the famous Matteson reaction or the late-stage borylative modification of alkynes or alkenes.Recently,the synthetic transformation of borylated building blocks offers another useful strategy and is currently actively explored.We report herein that B(MIDA)-propargylic alcohols(BPAs) are a useful type of borylated building blocks.Bearing two complementary functional group handles(alkyne and hydroxyl) in close proximity,the redox-neutral [3,3] and [2,3] sigmatropic rearrangements of BPAs allow the efficient synthesis of several types of α-functionalized boronates,including α,β-unsaturated acylborons,α-S/P-substituted allenylborons,boryl-substituted thiazoles and a borylated α,β-unsaturated hydrazine,some of which are otherwise challenging targets using other synthetic methods.

关键词： organoboron diverse synthesis sigmatropic rearrangement heteroarene amide

Design,synthesis and biological evaluation of fluorescent derivatives of ursolic acid in living cells

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Chinese Chemical Letters 2024年第5期35卷 287-289页

作者： Wenyi Mei Lijuan Xie Xiaodong Zhang Cunjian Shi Fengzhi Wang Qiqi Fu Zhenjiang Zhao Honglin Li Yufang Xu Zhuo Chen Shanghai Key Laboratory of New drug Design State Key Laboratory of Bioreactor EngineeringSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China Innovation center for AI and drug discovery East China Normal UniversityShanghai 200062China Lingang Laboratory Shanghai 200031China

Ursolic acid(UA)is a naturally occurring ursane triterpenoid,which exhibits a wide range of unique biological activities.To clarify its mechanism of action(MOA),a series of fluorescent derivatives of UA(5a-c)were designed and synthesized by conjugation with 7-nitrobenzo-2-oxa-1,3-diazole(NBD)fluorophore.Among them,5c exhibited similar anti-proliferative activity with UA against HCT116 cells(half maximal inhibitory concentration(IC_(50))=9.21±0.50μmol/L).Cell imaging experiment indicated that 5c was rapidly taken up in HCT116 cells in a dose and time-dependent manner.Then,5c was found to localize in endoplasmic reticulum(ER),lysosomes,and mitochondria,but not in nucleus of HCT116 cells by confocal microscopy studies.Preliminary MOA proved that UA induced autophagy with a unique intracellular distribution mechanism involving ER and lysosome.In all,our work provides new clues for revealing the molecular mechanism of UA as an antitumor agent.

关键词： Pentacyclic triterpenoid Ursolic acid Fluorescent derivatives Autophagy Apoptosis

SRY-Box transcription factor 9 triggers YAP nuclear entry via direct interaction in tumors

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2285-2297页

作者： Hui Qian Chen-Hong Ding Fang Liu Shi-Jie Chen Chen-Kai Huang Meng-Chao Xiao Xia-Lu Hong Ming-Chen Wang Fang-Zhi Yan Kai Ding Ya-Lu Cui Bai-Nan Zheng Jin Ding Cheng Luo Xin Zhang Wei-Fen Xie Department of Gastroenterology Changzheng HospitalNaval Medical UniversityShanghaiChina Department of Gastroenterology Shanghai East HospitalSchool of MedicineTongji UniversityShanghaiChina drug discovery and Design center CAS Key Laboratory of Receptor ResearchState Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina Department of Gastroenterology First Affiliated Hospital of Nanchang UniversityNanchangChina Clinical Cancer Institute Center for Translational MedicineNaval Medical UniversityShanghaiChina

The translocation of YAP from the cytoplasm to the nucleus is critical for its activation and plays a key role in tumor progression.However,the precise molecular mechanisms governing the nuclear import of YAP are not fully understood.In this study,we have uncovered a crucial role of SOX9 in the activation of YAP.SOX9 promotes the nuclear translocation of YAP by direct interaction.Importantly,we have identified that the binding between Asp-125 of SOX9 and Arg-124 of YAP is essential for SOX9-YAP interaction and subsequent nuclear entry of YAP.Additionally,we have discovered a novel asymmetrical dimethylation of YAP at Arg-124(YAP-R124me2a)catalyzed by PRMT1.YAP-R124me2a enhances the interaction between YAP and SOX9 and is associated with poor prognosis in multiple cancers.Furthermore,we disrupted the interaction between SOX9 and YAP using a competitive peptide,S-A1,which mimics anα-helix of SOX9 containing Asp-125.S-A1 significantly inhibits YAP nuclear translocation and effectively suppresses tumor growth.This study provides the first evidence of SOX9 as a pivotal regulator driving YAP nuclear translocation and presents a potential therapeutic strategy for YAP-driven human cancers by targeting SOX9-YAP interaction.

关键词： interaction. interaction precise

Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

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Cellular & molecular Immunology 2024年第3期21卷 292-308页

作者： Yiming Li Mingwei Han Haolin Wei Wan Huang Zhinan Chen Tianjiao Zhang Meirui Qian Lin Jing Gang Nan Xiuxuan Sun Shuhui Dai Kun Wang Jianli Jiang Ping Zhu Liang Chen Department of Cell Biology of National Translational Science center for molecular Medicine and Department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’anShaanxi 710032China State Key Laboratory of New Targets discovery and drug Development for Major Diseases GanzhouJiangxi341000Xi’anShaanxi 710032China School of Medicine Shanghai UniversityShanghai 200444China

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulations.Inhibitor of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell immunity.However,the role of Id2 in CD8^(+)T-cell exhaustion is unclear.Here,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells.Genetic deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor susceptibility.Mechanistically,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1.Therefore,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog cells.An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice.Inhibition of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T cells.This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

关键词： Id2 T-cell exhaustion Epigenetic modification Immune evasion

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA center for molecular Innovation and drug discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

Intelligent design and construction of novel APN-based theranostic probe driven by advanced computational methods

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Chinese Chemical Letters 2024年第2期35卷 352-357页

作者： Yingli Zhu Jie Qian Kunqian Yu Jing Hou Yeshuo Ma Fei Chen Jie Dong Wenbin Zeng Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410083China National Engineering Research center of Rice and Byproduct Deep Processing School of Food Science and EngineeringCentral South University of Forestry and TechnologyChangsha 410004China State Key Laboratory of drug Research Drug Discovery and Design CenterShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Geriatrics Third Xiangya HospitalCentral South UniversityChangsha 410013China

Multifunctional molecules with both optical signal and pharmacological activity play an important role in drug development,disease diagnosis,and basic theoretical research.Aminopeptidase N(APN),as a representative tumor biomarker with anti-tumor potential,still lacks a high-precision theranostic probe specifically targeting it.In this study,a novel quaternity design strategy for APN theranostic probe was developed.This proposed strategy utilizes advanced machine learning and molecular dynamics simulations,and cleverly employs the strategy of conformation-induced fluorescence recovery to achieve multi-objective optimization and integration of functional fragments.Through this strategy,a unique“Off-On”theranostic probe,ABTP-DPTB,was ingeniously constructed to light up APN through fluorescence restoration,relying on conformation-induced effects and solvent restriction.Differ from the common diagnostic probes,the intelligent design with non-substrated linkage makes ABTP-DPTB for long-term in-situ imaging.The fabricated probe was used for detecting and inhibiting APN in various environments,with a better in vitro inhibitory than golden-standard drug bestatin.

关键词： Theranostic probe Artificial intelligence Conformational restriction Fluorescence restoration Design strategy

Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2137-2152页

作者： Tarik Zahr Vijay K.Boda Jian Ge Lexiang Yu Zhongzhi Wu Jianwen Que Wei Li Li Qiang Naomi Berrie Diabetes center Columbia UniversityNew YorkNY 10032USA Department of molecular Pharmacology and Therapeutics Columbia UniversityNew YorkNY 10032USA Department of Pharmaceutical Sciences College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA drug discovery center College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA Division of Digestive and Liver Diseases Columbia UniversityNew YorkNY 10032USA center for Human Development Columbia UniversityNew YorkNY 10027USA Department of Pathology and Cell Biology Columbia UniversityNew YorkNY 10032USA Department of Medicine Columbia UniversityNew YorkNY 10032USA

Estrogen is imperative to mammalian reproductivity,metabolism,and aging.However,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain malignancies.In contrast,ERβis more broadly expressed in metabolic tissues and the skin.Thus,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERαactivation.Here,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or genistein.Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in vitro.We further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound healing.Therefore,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

关键词： Estrogen receptorβ Aging Metabolism Skin injury Muscle metabolism Small molecule conjugates Regeneration Adiposity

Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1651-1664页

作者： Xiong Xie Qiaoshuai Lan Jinyi Zhao Sulin Zhang Lu Liu Yumin Zhang Wei Xu Maolin Shao Jingjing Peng Shuai Xia Yan Zhu Keke Zhang Xianglei Zhang Ruxue Zhang jian Li Wenhao Dai Zhen Ge Shulei Hu Changyue Yu Jiang Wang Dakota Ma Mingyue Zheng Haitao Yang Gengfu Xiao Zihe Rao Lu Lu Leike Zhang Fang Bai Yao Zhao Shibo Jiang Hong Liu drug discovery and Design center State Key Laboratory of Drug ResearchCAS Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Medical molecular Virology(MOE/NHC/CAMS) School of Basic Medical SciencesShanghai Institute of Infectious Disease and BiosecurityFudan UniversityShanghai 200032China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China School of Chinese Materia Medica Nanjing University of Chinese Medicine138 Xian Lin RoadJiangsu 210023 NanjingChina School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced StudyUCASHangzhou 310024China National Clinical Research center for Infectious Disease Shenzhen Third People's HospitalShenzhen 518112China

Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their effcacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic a-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of a-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1.Both showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with ECso values ranging from 0.80 to 161.7 nM in various cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.In addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model.And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%.Further evaluation showed that 14a and 14b exhibited excellent antiinflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

关键词： calpain overcome entrance

Self-adjuvant Astragalus polysaccharide-based nanovaccines for enhanced tumor immunotherapy:a novel delivery system candidate for tumor vaccines

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Science China(Life Sciences) 2024年第4期67卷 680-697页

作者： Nan Li Yun Zhang Miaomiao Han Tian Liu Jinjia Wu Yingxia Xiong Yikai Fan Fan Ye Bing Jin Yinghua Zhang Guibo Sun Xiaobo Sun Zhengqi Dong State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Chinese Academy of Medical Sciences&Peking Union Medical College(CAMS)Institute of Medicinal Plant Development(IMPLAD)Beijing 100193China Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine from Ministry of Education Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine(Natural Medicine)and Translational MedicineKey Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription from Chinese Academy of Medical SciencesCAMSIMPLADBeijing 100193China Department of Pharmaceutics School of Pharmaceutical SciencesHeilongjiang University of Chinese MedicineHarbin 150036China Jilin Academy of Chinese Medicine Sciences Changchun 130012China Joint Research center for Chinese Medicinal Herbs IMPLADABRC&ACCLBeijing 100193China

The study of tumor nanovaccines(NVs)has gained interest because they specifically recognize and eliminate tumor cells.However,the poor recognition and internalization by dendritic cells(DCs)and insufficient immunogenicity restricted the vaccine efficacy.Herein,we extracted two molecular-weight Astragalus polysaccharides(APS,12.19 k D;APSHMw,135.67 k D)from Radix Astragali and made them self-assemble with OVA257–264directly forming OVA/APS integrated nanocomplexes through the microfluidic method.The nanocomplexes were wrapped with a sheddable calcium phosphate layer to improve stability.APS in the formed nanocomplexes served as drug carriers and immune adjuvants for potent tumor immunotherapy.The optimal APS-NVs were approximately 160 nm with uniform size distribution and could remain stable in physiological saline solution.The FITC-OVA in APS-NVs could be effectively taken up by DCs,and APS-NVs could stimulate the maturation of DCs,improving the antigen cross-presentation efficiency in vitro.The possible mechanism was that APS can induce DC activation via multiple receptors such as dectin-1 and Toll-like receptors 2 and 4.Enhanced accumulation of APS-NVs both in draining and distal lymph nodes were observed following s.***.injection.Smaller APS-NVs could easily access the lymph nodes.Furthermore,APS-NVs could markedly promote antigen delivery efficiency to DCs and activate cytotoxic T cells.In addition,APS-NVs achieve a better antitumor effect in established B16-OVA melanoma tumors compared with the OVA+Alum treatment group.The antitumor mechanism correlated with the increase in cytotoxic T cells in the tumor region.Subsequently,the poor tumor inhibitory effect of APS-NVs on the nude mouse model of melanoma also confirmed the participation of antitumor adaptive immune response induced by NVs.Therefore,this study developed a promising APS-based tumor NV that is an efficient tumor immunotherapy without systemic side effects.

关键词： Astragalus polysaccharides nanovaccines OVA immunotherapy self-adjuvant

Genome engineering of the human gut microbiome

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Journal of Genetics and Genomics 2024年第5期51卷 479-491页

作者： Linggang Zheng Juntao Shen Ruiyue Chen Yucan Hu Wei Zhao Elaine Lai-Han Leung Lei Dai Dr Neher's Biophysics Laboratory for Innovative drug discovery/State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyTaipaMacao 999078China CAS Key Laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China University of Chinese Academy of Sciences Beijing 100049China Cancer center Faculty of Health ScienceUniversity of MacaoMacao 999078China MOE Frontiers Science center for Precision Oncology University of MacaoMacao 999078China

The human gut microbiome,a complex ecosystem,significantly influences host health,impacting crucial aspects such as metabolism and immunity.To enhance our comprehension and control of the molecular mechanisms orchestrating the intricate interplay between gut commensal bacteria and human health,the exploration of genome engineering for gut microbes is a promising frontier.Nevertheless,the complexities and diversities inherent in the gut microbiome pose substantial challenges to the development of effective genome engineering tools for human gut microbes.In this comprehensive review,we provide an overview of the current progress and challenges in genome engineering of human gut commensal bacteria,whether executed in vitro or in situ.A specific focus is directed towards the advancements and prospects in cargo DNA delivery and high-throughput techniques.Additionally,we elucidate the immense potential of genome engineering methods to enhance our understanding of the human gut microbiome and engineer the microorganisms to enhance human health.

关键词： Non-model gut commensals Genomeediting reagents Cargo delivery high-throughput genome engineering