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Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1150-1165页

作者： Yuzhen Qian Yixuan Sun Peishang Shi Xiuman Zhou Qiongqiong Zhang Qingyu Dong Shengzhe Jin Lu Qiu Xiaoshuang Niu Xiaowen Zhou Wenshan Zhao Yahong Wu Wenjie Zhai Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China International Joint laboratory for protein and peptide Drugs of Henan Province Zhengzhou UniversityZhengzhou 450001China

Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower ***-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-1(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/***,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in ***,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γ *** importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune *** conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide synergizes with radiotherapy to further enhance the antitumor immune response.

关键词： LAG-3 FGL1 PD-1 PD-L1 peptide Immune checkpoint Radiotherapy Cancer immunotherapy

Rapid and sensitive detection of Epstein-Barr virus antibodies in nasopharyngeal carcinoma by chemiluminescence strips based on iron-porphyrin single atom nanozyme

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Nano Research 2024年第3期17卷 1827-1836页

作者： Daji Wang Jie Wang Dan Liu Jiuyang He Meiying Wang Haibing Huang Guohui Nie Hui Ding Xiyun Yan Nanozyme Synthesis Center Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Center for Drug Evaluation National Medical Products AdministrationBeijing 100022China Shenzhen key laboratory of nanozymes and Translational Cancer Research Department of Otolaryngologyand Shenzhen Institute of Translational MedicineShenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science CenterShenzhen 518035China CAS Engineering laboratory for Nanozyme Key Laboratory of Protein and Peptide PharmaceuticalInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China Department of Rheumatology and Immunology Shenzhen Second People’s HospitalThe First Affiliated Hospital of Shenzhen UniversityShenzhen 518055China

The correlation between Epstein-Barr virus(EBV)infection and nasopharyngeal carcinoma(NPC)risk has been extensively *** continual monitoring of EBV-IgAs provides a promising approach of NPC screening in its early *** this study,we successfully synthesized a single-atom nanozyme(SANzyme)through the application of iron-porphyrin based metal organic framework(MOF-FeP).The MOF-FeP possesses precisely-defined electronic and geometric structures that accurately mimic highly-evolved catalytic site of natural *** peroxidase-like activity of MOF-FeP enables it to catalyze the chemiluminescence of luminol *** integrating MOF-FeP into a traditional strip,we created a rapid and highly-sensitive evaluation tool for detecting ***,the MOF-FeP strip enables the simultaneous detection of three EBV-IgAs,greatly improving the accuracy of EBV-associated NPC *** sensitivities of the MOF-FeP strip(75.56%–93.30%)surpass those of current enzyme-linked immunosorbent assay(ELISA)methods(64.44%–82.22%).This test takes only 16 min to perform as opposed to the customary 1–2 h required for standard ***,the MOF-FeP strip is suitable for whole blood samples,thereby significantly simplifying the sample preparation and detection *** conclusion,the MOF-FeP strip combines the simplicity of traditional strip with the high catalytic activity of *** innovative MOF-FeP strip offers a new point-of-care strategy for EBV-IgAs detection,which is expected to markedly facilitate early screening for EBV-associated diseases.

关键词： iron-porphyrin single-atom nanozyme(SANzyme) chemiluminescence strips Epstein-Barr virus(EBV) nasopharyngeal carcinoma(NPC) antibody detection

Bioinspired metal-organic framework nanozyme reinforced with thermosensitive hydrogel for regulating inflammatory responses in Parkinson’s disease

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Nano Research 2024年第2期17卷 858-865页

作者： Xiaowan Fan Tao Zhang Xin Ding Yushuo Gu Qing Li Wei Jiang Kelong Fan Nanozyme Medical Center Academy of Medical ScienceZhengzhou UniversityZhengzhou 450001China Department Central-China Branch of National Center for Cardiovascular DiseasesHean Cardiovascular Disease CenterFuwai Central-China HospitalCentral China Fuwai Hospital of Zhengzhou UniversityZhengzhou 450046China Application Center for Precision Medicine the Second Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China CAS Engineering laboratory for Nanozyme Key Laboratory of Protein and Peptide PharmaceuticalsInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 101408China Department of General Surgery Strategic Support Force Medical CenterBeijing 100101China Department of Anesthesiology Pain and Perioperative MedicineThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052China

Parkinson’s disease(PD)is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory ***-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing ***,traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and ***,Cu-doping zeolite imidazolate framework-8(ZIF-8)nanozyme is designed to simulate Cu/Zn superoxide dismutase(SOD)by biomimetic *** nanozyme composite is then integrated into thermosensitive hydrogel(poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid)(PLGA-PEG-PLGA))to form an effective antioxidant system(Cu-ZIF@Hydrogel).The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion,prolonging nanozyme retention time,and modulating antioxidant activity,thus significantly improving the bioavailability of *** the cellular and animal levels of PD,we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve ***,the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion ***,the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.

关键词： bioinspired nanozyme thermosensitive hydrogel Parkinson’s disease oxidative stress neuroinflammatory

Computer-aided molecular design and optimization of potent inhibitors disrupting APC-Asef interaction

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2631-2645页

作者： Xuefei Wang Zeqian Du Yuegui Guo Jie Zhong Kun Song Junyuan Wang Jianqiang Yu Xiuyan Yang Chen-Ying Liu Ting Shi Jian Zhang Department of Pathophysiology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China key laboratory of Protection Development and Utilization of Medicinal Resources in Liupanshan AreaMinistry of EducationPeptide&Protein Drug Research CenterSchool of PharmacyNingxia Medical UniversityYinchuan 750004China State key laboratory of Microbial Metabolism Joint International Research Laboratory of Metabolic and Developmental SciencesSchool of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China Department of Colorectal and Anal Surgery Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Basic Science Research Center Base(Pharmaceutical Science) Yantai UniversityYantai 264005China Medicinal Chemistry and Bioinformatics Center Shanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China State key laboratory of Pharmaceutical Biotechnology Nanjing UniversityNanjing 210023China

Colorectal cancer(CRC)is the second leading cause of cancer mortality *** initial diagnosis,approximately 20%of patients are diagnosed with metastatic CRC(mCRC).Although the APC-Asef interaction is a well-established target for mCRC therapy,the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging *** this study,we identified a novel structural scaffold based on MAI inhibitors,the first-in-class APC-Asef inhibitors we reported *** model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed,and 24-fold greater potency was obtained with the best inhibitor compared to the parental *** addition,the cocrystal structure validated that the two-layerπ-πstacking interactions were essential for inhibitor stabilization in the bound ***,in vitro and in vivo studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC-Asef *** results provide an intrinsic structural basis to further explore drug-like molecules for APC-Asef-mediated CRC therapy.

关键词： APC-Asef Peptidomimetic Computer-aided molecular design ONIOM model π-πstacking Metastatic colorectal cancer

Active molecule-based theranostic agents for tumor vasculature normalization and antitumor efficacy

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Chinese Chemical Letters 2024年第8期35卷 229-234页

作者： Jin Wang Xiaoyan Pan Junyu Zhang Qingqing Zhang Yanchen Li Weiwei Guo Jie Zhang School of Pharmacy Health Science CenterXi’an Jiaotong UniversityXi’an 710061China Center of Advanced pharmaceuticals and Biomaterials State Key Laboratory of Natural MedicineChina Pharmaceutical UniversityNanjing 210009China

Tumor vascular normalization has emerged as a promising strategy for synergistic therapy *** on the strategy of“fluorescence turn on-controllable release”,a novel bifunctional candidate was con-structed based on previous developed vascular normalization inducer QDAU5,which could self-assemble to form functional enzyme infrared QDAU5 nanoparticles(FEIRQ NPs).Subsequently,biological evaluation demonstrated that the FEIRQ NPs could induce ferroptosis,endoplasmic reticulum stress,and antigen pre-conditioning and maturation of dendritic cells and CD8^(+)T cells,leading to excellent antitumor efficacy in the absence of cytotoxic ***,FEIRQ NPs show high fluorescence intensity upon expo-sure to theβ-galactosidase(β-Gal)enzyme expressed in ovarian cancer,enabling real-time monitoring of therapeutic ***,our findings suggest a prospering strategy to early diagnosis and efficient therapy for ovarian cancer without cytotoxicity.

关键词： Tumor vasculature normalization Diagnosis and treatment Cytotoxicity Depleting glutathione Ferroptosis Immune activation

ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第4期25卷 341-353页

作者： Zhibin YAN Ying SHI Runling YANG Jijun XUE Caiyun FU Zhejiang Provincial key laboratory of Silkworm Bioreactor and Biomedicine College of Life Sciences and MedicineZhejiang Sci-Tech UniversityHangzhou310018China State key laboratory of Applied Organic Chemistry College of Chemistry and Chemical EngineeringLanzhou University Lanzhou 730000China key laboratory of Preclinical Study for New Drugs of Gansu Province School of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical Sciences2019RU066Lanzhou UniversityLanzhou 730000China

Kidney fibrosis is an inevitable result of various chronic kidney diseases(CKDs)and significantly contributes to end-stage renal ***,there is no specific treatment available for renal ***13(amino acid sequence:RRCMPLHSRVPFP)is a conserved region of ELABELA in all vertebrates;however,its biological activity has been very little *** the present study,we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1(TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion(UUO)*** results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum,and reduce the expression of fibrosis biomarkers confirmed by Masson staining,immunohistochemistry,real-time polymerase chain reaction(RT-PCR),and western *** biomarkers were increased after UUO and decreased by administration of ***,we found that the levels of essential molecules in the mothers against decapentaplegic(Smad)and extracellular signal-regulated kinase(ERK)pathways were reduced by ELA13 treatment in vivo and in *** conclusion,ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

关键词： ELA13 Kidney fibrosis Inflammation Smad Extracllular signal-regulated kinase(ERK)

G protein-coupled receptors(GPCRs):advances in structures,mechanisms,and drug discovery

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1938-1980页

作者： Mingyang Zhang Ting Chen Xun Lu Xiaobing Lan Ziqiang Chen Shaoyong Lu key laboratory of Protection Development and Utilization of Medicinal Resources in Liupanshan AreaMinistry of EducationPeptide&Protein Drug Research CenterSchool of PharmacyNingxia Medical UniversityYinchuan 750004China Medicinal Chemistry and Bioinformatics Center Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Cardiology Changzheng HospitalAffiliated to Naval Medical UniversityShanghai 200003China Department of Orthopedics Changhai HospitalAffiliated to Naval Medical UniversityShanghai 200433China

G protein-coupled receptors(GPCRs),the largest family of human membrane proteins and an important class of drug targets,play a role in maintaining numerous physiological *** or antagonist,orthosteric effects or allosteric effects,and biased signaling or balanced signaling,characterize the complexity of GPCR dynamic *** this study,we first review the structural advancements,activation mechanisms,and functional diversity of *** then focus on GPCR drug discovery by revealing the detailed drug-target interactions and the underlying mechanisms of orthosteric drugs approved by the US Food and Drug Administration in the past five ***,an up-to-date analysis is performed on available GPCR structures complexed with synthetic small-molecule allosteric modulators to elucidate key receptor-ligand interactions and allosteric ***,we highlight how the widespread GPCR-druggable allosteric sites can guide structure-or mechanism-based drug design and propose prospects of designing bitopic ligands for the future therapeutic potential of targeting this receptor family.

关键词： steric designing mechanisms

Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1204-1221页

作者： Xiaohui Chen Meichun Gao Yongzhen Xia Xin Wang Jingbo Qin Hongying He Weirong Liu Xiaowei Zhang Shuangzhou Peng Zhiping Zeng Ying Su Xiaokun Zhang School of Pharmaceutical Science Fujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamen 361002China NucMito pharmaceuticals Co. Ltd.Xiamen 361000China Department of Clinical laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor *** pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to *** Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer ***,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 *** vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent *** studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related ***,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 ***,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

关键词： XS561 Nur77 Bcl-2 Apoptosis Mitochondria Phase separation TNBC TAMR

A kinetic resolution accompanied chirality transformation process for asymmetric synthesis of chiral phenol,oxaziridine,andα-hydroxyl cyclic ketone

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Science China Chemistry 2024年第9期67卷 2989-2997页

作者： Pengxin Wang Xiaoyong Zhang Lingqing Wang Rui Wang Dongxu Yang key laboratory of Preclinical Study for New Drugs of Gansu Province School of Basic Medical Sciences&Research Unit of Peptide ScienceChinese Academy of Medical SciencesLanzhou UniversityLanzhou 730000China State key laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China School of Sciences Great Bay UniversityDongguan 523000China Institute of Systems and Physical Biology Shenzhen Bay LaboratoryShenzhen 518055China

Chirality transformation is a basic,attractive,and important strategy for obtaining enantioenriched products with desired chiral *** reported chirality conversion reaction often involves the process from one type of chirality to another *** better utilize the chirality transformation strategy for obtaining two or more products with different chiral elements in a single reaction,a new method of kinetic resolution accompanied by a chirality transformation protocol is proposed and successfully realized in this *** process is used for the asymmetric oxidation of phenol compounds along with the kinetic resolution of oxaziridines.A wide scope of products,including axially chiral phenols,oxaziridines,andα-hydroxyl cyclic ketones were smoothly obtained in high levels of yields and enantioselectivities in the developed *** products can be readily used for the synthesis of various types of chiral ligands,which are potential choices for other catalytic asymmetric reactions.

关键词： chirality transformation kinetic resolution accompanied axially chiral phenols chiral oxaziridines

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