Journal of Medicinal Chemistry最新文献

{"title":"Preclinical Evaluation and Preliminary Clinical Study of Al18F-NOTA for PET/CT Imaging of Renal Function","authors":"Guangfa Wang,&nbsp;Xun Zhang,&nbsp;Wenhao Fu,&nbsp;Yakun Li,&nbsp;Yiming Mo,&nbsp;Qianhe Xu,&nbsp;Chaojun Wang,&nbsp;Rending Wang,&nbsp;Tianan Jiang,&nbsp;Nian Liu,&nbsp;Xinhui Su","doi":"10.1021/acs.jmedchem.6c01574","DOIUrl":"10.1021/acs.jmedchem.6c01574","url":null,"abstract":"<p>Accurate renal function assessment is crucial for kidney disease diagnosis and management, yet current methods lack real-time, quantitative <em>in vivo</em> evaluation. Capitalizing on the superior sensitivity and quantitative capabilities of fluorine-18 PET, we developed ¹⁸F-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (Al¹⁸F-NOTA) for the assessment of renal function. It was successfully radiosynthesized with high radiolabeling and low plasma protein binding. In healthy mice, Al¹⁸F-NOTA showed rapid renal clearance. In three distinct preclinical AKI models, PET imaging revealed significantly increased tracer accumulation in the injured kidneys and reduced GFR, which was validated by clinical laboratory techniques. A preliminary clinical study demonstrated rapid renal uptake and urinary excretion in healthy volunteers, whereas patients with renal dysfunction showed delayed clearance and increased renal retention. PET-derived renograms and GFR values were also consistent with clinical assessments, with no adverse effects observed. These findings establish Al¹⁸F-NOTA PET imaging as a highly promising, noninvasive diagnostic tool for assessing renal function.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22417–22426"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Innovative Auto-Antagonistic Multi-Target Strategy: MOR/DOR/NPFFR2 Agonists Achieve Separation of Analgesia from Side Effects","authors":"Pengtao Li,&nbsp;Yaofeng Zhao,&nbsp;Tong Yang,&nbsp;Lechun Ma,&nbsp;Zhanyu Niu,&nbsp;Zhonghua Zhang,&nbsp;Huiming Bao,&nbsp;Zhengkun Liu,&nbsp;Mingmin Huang,&nbsp;Hongyang Man,&nbsp;Shouliang Dong","doi":"10.1021/acs.jmedchem.6c02406","DOIUrl":"10.1021/acs.jmedchem.6c02406","url":null,"abstract":"<p>Long-term opioid analgesia is limited by severe adverse effects. We propose an auto-antagonistic multitarget strategy incorporating NPFFR₂-mediated counter-regulation to limit excessive opioid effects while preserving analgesia. Structure-guided optimization of MCRT yielded analogs <strong>1</strong>, <strong>4</strong>, and <strong>9</strong>, which function as MOR/DOR/NPFFR₂ triple agonists. Analog <strong>1</strong> provided pharmacological proof-of-concept, exhibiting characteristic bell-shaped antinociceptive and gastrointestinal dose−response profiles sensitive to RF-9 blockade. Together with its NPFFR₂ agonism and no detectable NPFFR₁ agonism <em>in vitro</em>, these findings support a contribution of NPFFR₂-mediated counter-regulation to its self-limiting profile. In contrast, analogs <strong>4</strong> and <strong>9</strong> displayed dose-dependent analgesia and distinct <em>in vivo</em> profiles. All three analogs produced robust antinociception in CFA-induced inflammatory pain and showed no detectable tolerance or persistent gastrointestinal inhibition during repeated treatment, while analogs <strong>1</strong> and <strong>4</strong> showed no detectable withdrawal, conditioned place preference, or motor impairment. These findings support the auto-antagonistic strategy as a framework for developing safer analgesics.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22972–22992"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Potent and Selective VHL-Recruiting PROTAC Degraders Targeting EGFR with Improved Developability and Potent Anti-NSCLC Efficacy","authors":"Xiang Ni,&nbsp;Mei Li,&nbsp;Jinglin Tang,&nbsp;Zhihao Qi,&nbsp;Ying Zhou,&nbsp;Zepeng Liao,&nbsp;Yiyun Song,&nbsp;Qi Miao,&nbsp;Zhiyi Zhang,&nbsp;Sheng Jiang,&nbsp;Yibei Xiao,&nbsp;Kuojun Zhang","doi":"10.1021/acs.jmedchem.6c01893","DOIUrl":"10.1021/acs.jmedchem.6c01893","url":null,"abstract":"<p>Epidermal growth factor receptor (EGFR) kinase inhibitors have revolutionized non-small cell lung cancer (NSCLC) treatment; however, the inevitable acquired resistance necessitates alternative strategies beyond conventional inhibition. Herein, we report the discovery and optimization of VHL-recruiting PROTAC degraders targeting the EGFR. Representative compounds <strong>C4</strong> and <strong>D4</strong> demonstrated potent, selective, and durable degradation of EGFR^Del19 (<strong>C4</strong>: DC₅₀ = 1.41 nM, <em>D</em>_max = 99%; <strong>D4</strong>: DC₅₀ = 9.14 nM, <em>D</em>_max = 98%) and EGFR^L858R (<strong>C4</strong>: DC₅₀ = 3.30 nM, <em>D</em>_max = 95%; <strong>D4</strong>: DC₅₀ = 15.2 nM, <em>D</em>_max = 98%). <strong>C4</strong> induced cell cycle arrest and apoptosis, displayed subnanomolar antiproliferative activity, and drove significant tumor regression in an HCC827 xenograft model at low intravenous doses with a reduced twice-weekly schedule. Remarkably, <strong>D4</strong> was orally bioavailable (<em>F</em> = 11.3%) and blood−brain barrier penetrant and completely inhibited tumor growth <em>in vivo</em> after oral dosing. Overall, this work provides promising starting points for next-generation EGFR-directed therapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22671–22698"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Selective ERα Photodegrader for Precise and Efficient Breast Cancer Treatment","authors":"Ziwei Wang,&nbsp;Xin Ding,&nbsp;Zhao Li,&nbsp;Yu Zhang,&nbsp;Qizhang Li,&nbsp;Kangkang Li,&nbsp;Jian Min,&nbsp;Juan Xu,&nbsp;Weidong Pan,&nbsp;Huan He,&nbsp;Chang Min,&nbsp;Silong Zhang","doi":"10.1021/acs.jmedchem.6c00904","DOIUrl":"10.1021/acs.jmedchem.6c00904","url":null,"abstract":"<p>Breast cancer is the most prevalent malignancy in women, with over 70% of cases being estrogen receptor α (ERα)-positive. Photodynamic therapy (PDT) is spatially precise yet limited by tumor-selective photosensitizers. Herein, we report the first co-crystal structure of 2,2′-dihydroxytriphenylamine bound to ERα, which provided a structural blueprint for designing <strong>EP5</strong>, an innovative ERα-targeted photodegrader. <strong>EP5</strong> exhibits high binding affinity toward ERα (<em>K</em>_D = 56.7 nM), enabling its selective accumulation in ERα-positive breast cancer cells. Upon white-light irradiation, EP5 triggers selective ERα degradation without affecting ERβ. It potently suppresses ERα-positive cancer cell proliferation (IC₅₀ = 0.54 μM, selectivity index &gt;185). Systemic EP5 administration plus light achieves complete xenograft tumor regression (TGI = 105.3%) with no detectable systemic toxicity. EP5 is a promising candidate for precision breast cancer therapy. By simultaneously achieving tumor selectivity, therapeutic efficacy, and safety, <strong>EP5</strong> represents a promising precision oncology platform for clinical translation.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"21902–21918"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated High-Throughput Ligand-Detected NMR for Medicinal Chemistry Hit Triage and Binding Assessment","authors":"Bradley Falk,&nbsp;Luciano Mueller,&nbsp;Erik Braunstein,&nbsp;Joanne Rivera,&nbsp;Christine Jorge,&nbsp;Purnima Khandelwal,&nbsp;Janet Caceres-Cortes","doi":"10.1021/acs.jmedchem.6c01749","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01749","url":null,"abstract":"<p>Early discovery campaigns routinely generate screening hits whose progression is limited by uncertain aqueous solubility, chemical integrity, and target engagement. We report a fully automated, ligand-detected high-throughput NMR (HT-NMR) workflow, applicable to aromatic-ring-containing compounds common to high throughput screening libraries, which delivers compound triage and binding assessment. Automated Echo/Tecan sample preparation is validated by Artel calibration and qNMR benchmarking, and band-selective SOFAST experiments centered on the aromatic region enable rapid acquisition in assay buffers. qNMR-SOFAST quantifies aqueous concentrations and flags degradation/impurities, while PE CPMG-SOFAST and STD-SOFAST provide orthogonal target engagement readouts. Python-based tools automate processing, analysis, and reporting. Ligand signals are detected down to 20 μM with quantitation error &lt;25%, allowing binding decisions to be made from as few as four paired samples, &lt;100 μg, per compound. A three-tier decision framework classifies hits by confidence and directs follow-up to orthogonal assays for affinity estimation, accelerating triage and reducing false progression.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22565–22573"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149125007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorination-Tuned Ionizable Lipids Regulate Nano-PROTAC Trafficking for Enhanced Targeted Protein Degradation","authors":"Junyao Li （李军瑶）,&nbsp;Huan Min （闵欢）,&nbsp;Yan Song （宋焱）,&nbsp;Rong Huo （霍荣）,&nbsp;Lin Du （杜琳）,&nbsp;Yongzheng Li （李永正）,&nbsp;Yajing Du （杜亚静）,&nbsp;Wei Ding （丁卫）,&nbsp;Yinlong Zhang （张银龙）,&nbsp;Yiye Li （李一叶）,&nbsp;Guangjun Nie （聂广军）,&nbsp;Yingqiu Qi （祁迎秋）","doi":"10.1021/acs.jmedchem.6c02116","DOIUrl":"10.1021/acs.jmedchem.6c02116","url":null,"abstract":"<p>Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF₃-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF₃-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF₃-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF₃-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF₃-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF₃-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.Nanoscale proteolysis-targeting chimeras (nano-PROTACs) offer modular platforms for targeted protein degradcine-rich α-2-glycoprotein 1 (LRG1). i16αCF₃-LipoTAC showed greater degradation potend endocytosis, and promoted endosomal escape. In 4T1 tumor models, i16αCF₃-LipoTAC prolonged circulation, increased tumor accumulation and target depletion, and improved antitumor efficacy. These findings support fluorination tuning as a strategy to enhance nano-PROTAC trafficking and degradation efficiency.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22907–22924"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"β-Sheet Antimicrobial and Antimycobacterial Peptides with a High Therapeutic Index by Employing the Repeats of a 5-Mer Segment of α-Helical Cytolytic Melittin","authors":"Rahul Dev Verma,&nbsp;Sariyah Akhtar,&nbsp;Jyotshana Saroj,&nbsp;Juhi Sharma,&nbsp;Mohd Mustkim Ansari,&nbsp;Rahul Verma,&nbsp;Animesh Chaurasia,&nbsp;Mohammad Imran Siddiqi,&nbsp;Bhupendra Narain Singh,&nbsp;Kalyan Mitra,&nbsp;Jimut Kanti Ghosh","doi":"10.1021/acs.jmedchem.6c01498","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01498","url":null,"abstract":"<p>Despite strong antimicrobial activity, high haemolytic/cytotoxic properties, associated with its non-cell-selective membrane-lytic property and its large size prohibits considering bee-venom, α-helical, 26-residue, melittin as a lead molecule for antimicrobial-drug development. Herein, we have explored the design of shorter non-haemolytic/non-cytotoxic antimicrobial peptides with low hydrophobic/amphipathic property and β-sheet secondary structure by using a 5-mer carboxy-terminus melittin segment, “WIKRK”, which contains hydrophobic and polar-cationic residues at its two ends. Three peptides, 10-mer, MLT-1, 15-mer, MLT-2, and 20-mer, MLT-3 were designed by taking two, three, and four repeats of “WIKRK”, respectively. MLT-2 and MLT-3 showed β-sheet secondary structure in bacterial membrane-mimetic lipid-vesicles, exhibited negligible haemolytic/cytotoxic properties in comparison to melittin, demonstrated significant antibacterial activities with high therapeutic indexes, and showed anti-mycobacterial activities against a fast/slow-growing strain. Further, MLT-2 and MLT-3 showed appreciable in vivo efficacy against Escherichia coli American Type Culture Collection 25922-infection in mice in the intravenous route and inhibited transcription/translation in in vitro assays suggesting their intracellular mode of action.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22370–22390"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting LSD1 Modulates Therapeutic Responses to Nucleoside Analogues: From Myeloid Malignancies to Viral Infections","authors":"Xiaoshuang Niu,&nbsp;Xiangyu Xu,&nbsp;Haibin Yu,&nbsp;Bin Yu","doi":"10.1021/acs.jmedchem.6c02818","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c02818","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"21545–21550"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Vanadium(II) Photosensitizer Delivered by Human Serum Albumin for Photodynamic Therapy","authors":"Zisis Papadopoulos,&nbsp;Aimée Marie Irgel,&nbsp;Alexandra König-Schäfer,&nbsp;Katja Heinze,&nbsp;Johannes Karges","doi":"10.1021/acs.jmedchem.6c01764","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c01764","url":null,"abstract":"<p>Photodynamic therapy (PDT) is an established clinically approved treatment; however, the development of next-generation photosensitizers remains constrained by the reliance on scarce precious-metal scaffolds and poor pharmacological properties. Earth-abundant first−row transition metals offer an attractive alternative, but their application in PDT remains underexplored. Herein, we report the first vanadium(II) photosensitizer for PDT and show that its biological activity can be unlocked through loading into human serum albumin (HSA), a strategy intended to improve its pharmacological properties. The resulting HSA-bound complex showed negligible dark toxicity and induced pronounced light-dependent cytotoxicity upon blue- and red-light irradiation in human colon carcinoma cells. Mechanistic studies revealed that the HSA-bound complex preferentially accumulates in lysosomes, where red-light irradiation triggers singlet oxygen generation and promotes apoptosis. This work establishes vanadium(II) complexes as a new class of photosensitizers for photodynamic therapy and opens new opportunities for the design of first-row transition-metal photosensitizers with improved photophysical properties.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"22574–22585"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149125027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2","authors":"Vincenzo Di Lorenzo,&nbsp;Noémi Csorba,&nbsp;Renáta Szabó,&nbsp;Levente Kollár,&nbsp;Yvette Roske,&nbsp;Ivan Rand̵elović,&nbsp;Krisztina Balázs,&nbsp;Tibor Viktor Szalai,&nbsp;Nina-Louisa Efrém,&nbsp;Levente Mihalovits,&nbsp;Tímea Imre,&nbsp;József Simon,&nbsp;József Tóvári,&nbsp;Marc Nazaré,&nbsp;Oliver Daumke,&nbsp;Péter Ábrányi-Balogh,&nbsp;György M. Keserű","doi":"10.1021/acs.jmedchem.6c01030","DOIUrl":"10.1021/acs.jmedchem.6c01030","url":null,"abstract":"<p>Covalent mechanism of action is a powerful way to modulate challenging drug targets. Here, we present a streamlined workflow that combines covalent fragment screening (electrophile first approach) and ligand-first strategy to identify covalent inhibitors targeting lysine residues in the allosteric latch site of SHP2 phosphatase. Supported by complementary computational and experimental analyses, this strategy enabled us to identify the first potent cell active allosteric covalent inhibitors acting at this site. Demonstrating the covalent tractability of the latch site opens further avenues for future optimization and therapeutic exploration of high-value allosteric SHP2 inhibitors.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"69 19","pages":"21955–21971"},"PeriodicalIF":7.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149003513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}