ChemMedChem最新文献_第10页

CD4 Mimic-Neutralizing Antibody Conjugates Synthesized by Site-Specific Modification Methods as HIV-1 Entry Inhibitors 通过位点特异性修饰方法合成CD4模拟中和抗体偶联物作为HIV-1进入抑制剂

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.202500820

Kohei Tsuji, Yutaro Miura, Takeo Kuwata, Riku Matsuzaki, Takuya Kobayakawa, Kaho Matsumoto, Yuji Ito, Taku Yoshiya, Shuzo Matsushita, Hirokazu Tamamura

{"title":"CD4 Mimic-Neutralizing Antibody Conjugates Synthesized by Site-Specific Modification Methods as HIV-1 Entry Inhibitors","authors":"Kohei Tsuji, Yutaro Miura, Takeo Kuwata, Riku Matsuzaki, Takuya Kobayakawa, Kaho Matsumoto, Yuji Ito, Taku Yoshiya, Shuzo Matsushita, Hirokazu Tamamura","doi":"10.1002/cmdc.202500820","DOIUrl":"https://doi.org/10.1002/cmdc.202500820","url":null,"abstract":"Antibody-drug conjugates (ADCs) that equip multiple cytotoxic drugs on an antibody have been developed, particularly in cancer chemotherapy. In the treatment of viral infectious diseases, there are dominantly fewer examples of ADCs. Recently, we developed double-warhead ADCs targeting the entry of human immunodeficiency virus type 1 (HIV-1) into host cells. One is a small molecule CD4 mimic, which is a competitive inhibitor against the interaction between a viral envelop protein, gp120, and a primary receptor, CD4, and the other is neutralizing antibodies, which recognize the regions of gp120, exposed by its conformational change after the interaction between gp120 and CD4. The conformational changes are also triggered by the binding of gp120 and a CD4 mimic, and therefore, the ADCs show positive effects on anti-HIV-1 activity compared to the combinational use of CD4 mimics with neutralizing antibodies. Herein, we synthesized novel ADCs containing a CD4 mimic and a neutralizing antibody, KD-247, using tCAP chemistry, which is based on a site-specific modification method for IgG antibodies, and evaluated their anti-HIV-1 and antibody-dependent cellular cytotoxicity (ADCC) activities. As a result, the KD-247-adopted ADCs demonstrated enhanced anti-HIV-1 activities, whereas all of the ADCs reduced their ADCC activities.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Donor–Donor-π-Acceptor–Acceptor Type Photosensitizer for Efficient Photo-Inactivation of Pathogens Within Biofilms and Host Cells 一种用于生物膜和宿主细胞内病原体光失活的供体-供体-π-受体-受体型光敏剂

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.202500703

Yunli Xu, Kun Wang, Yao Wu, Xuwen Da, Lingqing Yang, Yishan Yao, Xuesong Wang, Qianxiong Zhou

{"title":"A Donor–Donor-π-Acceptor–Acceptor Type Photosensitizer for Efficient Photo-Inactivation of Pathogens Within Biofilms and Host Cells","authors":"Yunli Xu, Kun Wang, Yao Wu, Xuwen Da, Lingqing Yang, Yishan Yao, Xuesong Wang, Qianxiong Zhou","doi":"10.1002/cmdc.202500703","DOIUrl":"https://doi.org/10.1002/cmdc.202500703","url":null,"abstract":"Antibacterial photodynamic therapy (aPDT) is a promising strategy for combating prevalent antibiotic-resistant bacteria. However, development of efficient aPDT agents that can simultaneously eradicate resistant pathogens within biofilms and host cells with good biocompatibility remains a big challenge. Herein, three novel D–D-π-A–A type dyes (TPATA, TPATC, and TPATPy) were designed and synthesized. TPATPy can efficiently produce reactive oxygen species (ROS) mainly through type I mechanism, which is beneficial for overcoming hypoxia within biofilms. Besides, introduction of pyridinium cations in TPATPy enhances the binding ability with negatively charged bacteria and biofilms through electrostatic interactions. Therefore, TPATPy not only exhibited excellent aPDT activity toward planktonic bacteria, but also destroyed mature biofilms and the embedded pathogens. Moreover, TPATPy could selectively and efficiently photo-inactivate intracellular methicillin-resistant Staphylococcus aureus (MRSA), being more potent than vancomycin. So far as we know, TPATPy should be the first example that can simultaneously eradicate intractable pathogens within biofilms and host cells. The efficacy and safety of TPATPy in accelerating wound healing have also been demonstrated in an MRSA-infected skin wound model in mice. These results may provide new ideas for developing multifunctional aPDT agents to solve the intractable problems in antibacterial treatment.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

One-Step Assembly of Homogeneous DAR4 ADCs via a Traceless Fc Ligand-Directed Acylation Strategy 通过无迹Fc配体定向酰化策略一步组装均相DAR4 adc

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.202501075

Yue Zeng, Yuyu Lin, Qi Sun, Jiaying Hang, Wei Shi, Wei Huang, Feng Tang

{"title":"One-Step Assembly of Homogeneous DAR4 ADCs via a Traceless Fc Ligand-Directed Acylation Strategy","authors":"Yue Zeng, Yuyu Lin, Qi Sun, Jiaying Hang, Wei Shi, Wei Huang, Feng Tang","doi":"10.1002/cmdc.202501075","DOIUrl":"https://doi.org/10.1002/cmdc.202501075","url":null,"abstract":"Site-specific antibody-drug conjugates (ADCs) represent a promising class of biotherapeutics with enhanced pharmacological profiles. we herein report a novel one-step strategy for preparing homogeneous ADCs with a drug-to-antibody ratio (DAR) of 4. This approach leverages a Fc ligand-directed thioester-based acylating reagent combined with a β-glutamic acid-based branching linker to enable precise conjugation of four MMAE molecules per antibody. Through systematic optimization of buffer composition and pH, we successfully mitigated the hydrophobicity-driven aggregation typically associated with K248-linked DAR4 ADCs, while maintaining exceptional conjugation efficiency. The method demonstrates excellent tolerance to protein concentration and is applicable to multiple IgG subtypes, including those targeting HER2, cMet, ROR1, and FRα. All resulting ADC products exhibited high homogeneity. Notably, ADC-4, functionalized with a VK(SO3H)-modified linker, showed enhanced aggregation stability, potent tumor suppression, and a favorable safety profile, highlighting its promising therapeutic potential.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Front Cover: Polydopamine-Based Light Responsive Nanoparticles with Magnetic Resonance Imaging Capabilities for Breast Cancer Photodynamic/Photothermal Therapy Combination Therapy (ChemMedChem 3/2026) 封面：具有磁共振成像能力的聚多巴胺光响应纳米颗粒用于乳腺癌光动力/光热联合治疗（ChemMedChem 3/2026）

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.70235

Yupeng Zhang, Mengke Lu, Yingying Chen, Ziyi Wang, Wei Zhang

引用次数: 0

Sculpting Cell Fate: The Expanding Universe of Nondegradative Proximity-Inducing Tools 雕刻细胞的命运：不可降解的接近诱导工具的扩展宇宙

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.202501088

Hangdi Xiao, Lan Wang, Mengxiao Chen, Tengfei Zhen, Yao Chen, Haopeng Sun

{"title":"Sculpting Cell Fate: The Expanding Universe of Nondegradative Proximity-Inducing Tools","authors":"Hangdi Xiao, Lan Wang, Mengxiao Chen, Tengfei Zhen, Yao Chen, Haopeng Sun","doi":"10.1002/cmdc.202501088","DOIUrl":"https://doi.org/10.1002/cmdc.202501088","url":null,"abstract":"The paradigm of targeted therapy has been revolutionized by the development of proximity-inducing chimeras, particularly proteolysis-targeting chimeras (PROTACs), which offer a therapeutic strategy for previously “undruggable” targets. However, the degradation of certain essential proteins can lead to off-target toxicity, prompting the development of nondegradative proximity-inducing chimeras. This review categorizes current nondegradative chimeras into several functional classes, including targeted inhibition, targeted stabilization, post-translational modification (PTM), and cellular switches; elaborates on the mechanisms of action for each category; and introduces representative technologies, including molecular glues (MGs). Furthermore, the review highlights cutting-edge research and recent advancements in the field. Unlike previous reviews focusing primarily on degradative chimera technologies, this article systematically categorizes nondegradative modalities into inhibition, stabilization, PTM, and cellular switches, providing a unified mechanistic framework and highlighting emerging therapeutic applications beyond oncology.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146162591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polymethoxylated N-Carboranyl Isoquinolinones: A New Scaffold for ABCG2 Inhibitors 多甲氧基n -碳硼基异喹啉酮：ABCG2抑制剂的新支架。

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.202500708

Lydia Kuhnert, Philipp Stockmann, Peter Lönnecke, Mara Anna Wolniewicz, Evamarie Hey-Hawkins, Walther Honscha

{"title":"Polymethoxylated N-Carboranyl Isoquinolinones: A New Scaffold for ABCG2 Inhibitors","authors":"Lydia Kuhnert, Philipp Stockmann, Peter Lönnecke, Mara Anna Wolniewicz, Evamarie Hey-Hawkins, Walther Honscha","doi":"10.1002/cmdc.202500708","DOIUrl":"10.1002/cmdc.202500708","url":null,"abstract":"ABCG2-mediated multidrug resistance (MDR) is a major challenge among chemotherapeutic treatments of colon, pancreatic, and breast cancer, as well as leukemia. Clinical oncology seeks new adjuvant therapeutics to overcome MDR by developing potent but nontoxic ABCG2 inhibitors. Aided by computational docking analyses, based on known substrate and inhibitor structural motifs, a new isoquinolinone framework and several (poly)methoxylated derivatives were designed and synthesized. The novel carborane-containing N-carboranyl isoquinolinones were evaluated for cytotoxicity, ABCG2 inhibition, and reversal of MDR in combination with mitoxantrone (MXN) in an ABCG2-expressing Madin–Darby canine kidney II cell model. While the parental compound IC-1 showed strong ABCG2 inhibition, its 4-methoxyphenyl, 3,4-dimethoxyphenyl, and 3,4,5-trimethoxyphenyl derivatives (IC-4, IC-5, and IC-6) exhibited improved ABCG2 affinity. Nonsubstituted isoquinolinones IC-1 to IC-6 displayed higher solubility, lower toxicity, and similar ABCG2 inhibition and reversal of MXN resistance than 6,7-dimethoxy-isoquinolinone derivatives IC-7 to IC-11. Especially, the 4-methoxyphenyl- and 3,4-dimethoxyphenyl-substituted isoquinolinones (IC-10, IC-11) caused the strongest left shift of the MXN IC50 value by 8.1- and 7.2-fold, indicating effective resensitization to the chemotherapeutic agent. Therefore, carborane-containing isoquinolinones featuring additional methoxy groups represent a promising approach for the development of ABCG2 inhibitors to overcome resistance to anticancer drugs.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://chemistry-europe.onlinelibrary.wiley.com/doi/epdf/10.1002/cmdc.202500708","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Boron Clusters Versus Adamantane: A Comparative Study of Inorganic and Organic Scaffolds Against Resistant Influenza A 硼簇与金刚烷：无机和有机支架对抗耐药甲型流感的比较研究

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.202501051

Timur M. Garaev, Ilya I. Yudin, Natalya V. Breslav, Elena I. Burtseva, Tatyana V. Grebennikova, Evgenii Yu. Matveev, Elizaveta A. Eshtukova-Shcheglova, Varvara V. Avdeeva, Konstantin Yu. Zhizhin

{"title":"Boron Clusters Versus Adamantane: A Comparative Study of Inorganic and Organic Scaffolds Against Resistant Influenza A","authors":"Timur M. Garaev, Ilya I. Yudin, Natalya V. Breslav, Elena I. Burtseva, Tatyana V. Grebennikova, Evgenii Yu. Matveev, Elizaveta A. Eshtukova-Shcheglova, Varvara V. Avdeeva, Konstantin Yu. Zhizhin","doi":"10.1002/cmdc.202501051","DOIUrl":"https://doi.org/10.1002/cmdc.202501051","url":null,"abstract":"A series of adamantane-based amino acid derivatives incorporating γ-aminobutyric acid (GABA) as a spacer, with the general structure Ad-CH2-CO-GABA-X-OMe (where X represents L-tryptophan (Trp), L-histidine (His), H-Ala-((S)-2-oxopyrrolidin-3-yl)-OMe (Pld), or L-methionine (Met)), were synthesized and evaluated in vitro for their antiviral activity against rimantadine-resistant influenza A virus strains A/Moscow/78/2020(H1N1)pdm09 and A/Cheboksary/125/2020(H1N1)pdm09. The results demonstrated that the presence of an L-tryptophan residue is crucial for effective inhibition of influenza virus replication, with the corresponding derivative exhibiting potent activity at an IC50 of 0.5 µg/mL. A comparative analysis of structural features and antiviral properties was conducted between the adamantane derivatives and analogous derivatives of the closo-decaborate anion ([B10H10]2–) functionalized with identical amino acid residues Na2[B10H9–O(CH2)2O(CH2)3C(O)–X–OCH3] (X = Trp, His) and spacers of comparable length. This study suggests that combining adamantane-based compounds with closo-decaborate clusters could lead to the development of highly effective therapeutic compositions with enhanced efficacy and improved safety profiles.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":"21 3","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146162590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Biological Evaluation of Pseudo-Natural Products Inspired by Aryloctahydroindole Alkaloids 芳基氢吲哚生物碱类伪天然产物的设计、合成和生物学评价

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-12 DOI: 10.1002/cmdc.202501102

Luca C. Greiner, Freddy A. Bernal, Sasikala Thavam, Maite Brachthäuser, Sonja Sievers, Slava Ziegler, Herbert Waldmann

引用次数: 0

Cover Feature: Nonstandard Factor VIIa Binding Mode Reveals S1 Pocket Plasticity in Trypsin-Like Proteases (ChemMedChem 3/2026) 封面专题：非标准因子via结合模式揭示胰蛋白酶样蛋白酶S1口袋可塑性（ChemMedChem 3/2026）

IF 3.4 4区医学

ChemMedChem Pub Date : 2026-02-11 DOI: 10.1002/cmdc.70236

Laura Tesmer, Hans Matter, Otmar Klingler, Manfred Schudok, Gerhard Hessler, Ahmad Reza Mehdipour, Stefan Güssregen, Herman Schreuder, Gerhard Hummer

引用次数: 0

A Metal–Organic Nanoplatform Coassembled with Artesunate and Chlorin e6 for Synergistic Chemo/Photodynamic Cancer Therapy 与青蒿琥酯和氯e6协同组装的金属-有机纳米平台用于协同化疗/光动力癌症治疗。