Bioorganic & Medicinal Chemistry最新文献

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Quantitative and site-specific chemoproteomic profiling of O-GlcNAcylation in Drosophila

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-04-10 DOI: 10.1016/j.bmc.2025.118191

Cong Lei , Zihan Chen , Yi Hao , Wanping Huang , Tianyu Chu , Kangming Xiao , Che Zhang , Wen Zhou , Chenjian Li , Xing Chen

Protein O-GlcNAcylation plays a crucial role in Drosophila melanogaster development. Dysregulation of O-GlcNAc transferase (sxc/Ogt) and O-GlcNAcase (Oga) disrupts early embryogenesis and locomotor behavior. It is therefore of great interest to identify and quantitatively analyze O-GlcNAcylation sites in Drosophila. Here, we perform quantitative and site-specific profiling of O-GlcNAcylation in Drosophila by employing a chemoenzymatic labeling strategy. A total of 2196 unambiguous O-GlcNAcylation sites and 1308 O-GlcNAcylated proteins are identified. Quantitative analysis of O-GlcNAcylation in the head of Drosophila with sxc/Ogt knockdown in GABAergic neurons reveals a reduction in O-GlcNAcylation of several proteins involved in muscle development, consistent with the phenotypic defects observed in sxc/Ogt RNAi Drosophila. Furthermore, quantitative analysis of O-GlcNAcylation under a high-sugar diet reveals altered O-GlcNAcylation of several proteins associated with obesity and neurological diseases, such as Hex-A and Ankyrin 2. Our study not only establishes an effective method for large-scale identification of O-GlcNAcylation sites, but also provides a valuable resource for studying O-GlcNAc biology in Drosophila.

{"title":"Quantitative and site-specific chemoproteomic profiling of O-GlcNAcylation in Drosophila","authors":"Cong Lei , Zihan Chen , Yi Hao , Wanping Huang , Tianyu Chu , Kangming Xiao , Che Zhang , Wen Zhou , Chenjian Li , Xing Chen","doi":"10.1016/j.bmc.2025.118191","DOIUrl":"10.1016/j.bmc.2025.118191","url":null,"abstract":"<div><div>Protein O-GlcNAcylation plays a crucial role in <em>Drosophila melanogaster</em> development. Dysregulation of O-GlcNAc transferase (<em>sxc</em>/<em>Ogt</em>) and O-GlcNAcase (<em>Oga</em>) disrupts early embryogenesis and locomotor behavior. It is therefore of great interest to identify and quantitatively analyze O-GlcNAcylation sites in <em>Drosophila</em>. Here, we perform quantitative and site-specific profiling of O-GlcNAcylation in <em>Drosophila</em> by employing a chemoenzymatic labeling strategy. A total of 2196 unambiguous O-GlcNAcylation sites and 1308 O-GlcNAcylated proteins are identified. Quantitative analysis of O-GlcNAcylation in the head of <em>Drosophila</em> with <em>sxc</em>/<em>Ogt</em> knockdown in GABAergic neurons reveals a reduction in O-GlcNAcylation of several proteins involved in muscle development, consistent with the phenotypic defects observed in <em>sxc</em>/<em>Ogt</em> RNAi <em>Drosophila</em>. Furthermore, quantitative analysis of O-GlcNAcylation under a high-sugar diet reveals altered O-GlcNAcylation of several proteins associated with obesity and neurological diseases, such as Hex-A and Ankyrin 2. Our study not only establishes an effective method for large-scale identification of O-GlcNAcylation sites, but also provides a valuable resource for studying O-GlcNAc biology in <em>Drosophila</em>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118191"},"PeriodicalIF":3.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Development of GluN2A NMDA receptor positive allosteric modulators: Recent advances and perspectives

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-04-10 DOI: 10.1016/j.bmc.2025.118194

Ping Li , Jiacheng Wang , Mengjiao Wang , Xin Chen , Hongyu Zhu , Mingxin Dong

N-methyl-d-aspartate (NMDA) receptors, functioning as glutamate-gated ion channels, mediate the permeation of Ca²⁺ and are essential for excitatory synaptic transmission and synaptic plasticity within the central nervous system (CNS). During brain development, there is a switch from an early dominance of GluN2B subunit expression to the incorporation of GluN2A subunits at mature synapses. NMDARs hypofunction is implicated in various psychiatric disorders, and activation of NMDARs containing GluN2A has recently attracted attention as a promising therapeutic approach for treating these diseases. This review focuses on the selective positive allosteric modulators (PAMs) that specifically target the ligand-binding domain (LBD) and N-terminal domain (NTD) regions of GluN2A subtype, as well as non-subunit selective PAMs, and discusses their implications in neuropsychiatric diseases such as stroke, depression, Alzheimer’s disease, and Huntington’s disease.

引用次数: 0

Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode 具有三点锁定结合模式的 Autotaxin 抑制剂的设计、合成及其生物学意义

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-04-07 DOI: 10.1016/j.bmc.2025.118181

Nicolas Desroy , Razvan Borza , Jörg Heiermann , Nicolas Triballeau , Agnès Joncour , Natacha Bienvenu , Willem Jan Hengeveld , Jasper Springer , René Galien , Robbie P. Joosten , Anastassis Perrakis , Bertrand Heckmann

Autotaxin (ATX) is a circulating enzyme that plays a major role in the production of the signaling mediator lysophosphatidic acid (LPA). A role for ATX/LPA signaling has been described in multiple disease areas, including fibrosis and cancer. ATX inhibitors are classified in five types (I-V) depending on how they target parts of the tripartite site (active site, pocket and tunnel). We set to explore a “penultimate” type of inhibitors, targeting all these three parts at once. Designing new analogs extending on an ethyl group of the type IV GLPG1690 compound, yielded potent new molecules. Co-crystal structures confirmed compounds that utilize a three-point lock binding mode. The most potent “type VI” inhibitors, 4 and 41, displayed increased inhibitory activity (∼40-fold) compared to the type IV close analog 3. Type VI inhibitors 4 and 41 showed cellular and phenotypic activity similar to type IV inhibitor GLPG1690. Identification of this new binding mode completes this combinatorial puzzle in inhibitor design and calls for further investigation to characterize potential therapeutic benefit.

{"title":"Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode","authors":"Nicolas Desroy , Razvan Borza , Jörg Heiermann , Nicolas Triballeau , Agnès Joncour , Natacha Bienvenu , Willem Jan Hengeveld , Jasper Springer , René Galien , Robbie P. Joosten , Anastassis Perrakis , Bertrand Heckmann","doi":"10.1016/j.bmc.2025.118181","DOIUrl":"10.1016/j.bmc.2025.118181","url":null,"abstract":"<div><div>Autotaxin (ATX) is a circulating enzyme that plays a major role in the production of the signaling mediator lysophosphatidic acid (LPA). A role for ATX/LPA signaling has been described in multiple disease areas, including fibrosis and cancer. ATX inhibitors are classified in five types (I-V) depending on how they target parts of the tripartite site (active site, pocket and tunnel). We set to explore a “penultimate” type of inhibitors, targeting all these three parts at once. Designing new analogs extending on an ethyl group of the type IV GLPG1690 compound, yielded potent new molecules. Co-crystal structures confirmed compounds that utilize a three-point lock binding mode. The most potent “type VI” inhibitors, <strong>4</strong> and <strong>41</strong>, displayed increased inhibitory activity (∼40-fold) compared to the type IV close analog <strong>3</strong>. Type VI inhibitors <strong>4</strong> and <strong>41</strong> showed cellular and phenotypic activity similar to type IV inhibitor GLPG1690. Identification of this new binding mode completes this combinatorial puzzle in inhibitor design and calls for further investigation to characterize potential therapeutic benefit.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118181"},"PeriodicalIF":3.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 and identification of brain-penetrant, potent, and selective 1,3-oxazole-based cholesterol 24-hydroxylase (CH24H) inhibitors

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-04-05 DOI: 10.1016/j.bmc.2025.118182

Yoshiteru Ito , Eiji Kimura , Izumi Nomura , Etsurou Watanabe , Jason Yano , Robert Skene , Maki Miyamoto , Tsuyoshi Ishii , Toshiya Nishi , Tatsuki Koike

Azole-, pyridine-, and pyrimidine-based cytochrome P450 (CYP) inhibitors strongly bind to CYP enzymes through the coordination between the heme iron of CYP and the sp2-nitrogen atoms of heteroaromatic rings, providing potent pharmacological effects by inhibiting the initiation of the catalytic cycles of target CYP enzymes. Although imidazole-, 1,2,4-triazole-, pyridine-, and pyrimidine-based CYP inhibitors have been widely explored, 1,3-oxazole-based CYP inhibitors have received little attention. In this study, we designed and identified novel 1,3-oxazole-based inhibitors of cholesterol 24- hydroxylase (CH24H; CYP46A1), a brain-specific enzyme involved in cholesterol catabolism, to form 24S-hydroxycholesterol. Detailed insights into the CH24H–ligand interactions were provided by the crystal structures of 1,3-oxazole compounds, including high-throughput screening hit 2 and rationally designed inhibitor 3f. Optimization of 3f led to the identification of 1,3-oxazole derivative 4 l as a potent, selective, and brain-penetrable CH24H inhibitor that significantly reduced 24HC levels in the mouse brain. The design of 1,3-oxazole-based CYP inhibitors holds the potential for the discovery of novel inhibitors with significant potency against a broad spectrum of CYP enzymes.

唑类、吡啶类和嘧啶类细胞色素 P450（CYP）抑制剂通过 CYP 的血红素铁和杂芳环的 sp2-氮原子之间的配位与 CYP 酶紧密结合，通过抑制目标 CYP 酶催化循环的启动而产生强效药理作用。虽然咪唑类、1,2,4-三唑类、吡啶类和嘧啶类 CYP 抑制剂已被广泛研究，但 1,3-oxazole 类 CYP 抑制剂却很少受到关注。在这项研究中，我们设计并鉴定了新型 1,3-噁唑类胆固醇 24- 羟化酶（CH24H；CYP46A1）抑制剂，该酶是一种大脑特异性酶，参与胆固醇分解代谢，形成 24S- 羟基胆固醇。1,3-噁唑化合物的晶体结构，包括高通量筛选结果 2 和合理设计的抑制剂 3f，提供了有关 CH24H 与配体相互作用的详细见解。对 3f 进行优化后，发现 1,3-噁唑衍生物 4 l 是一种强效、选择性和脑穿透性 CH24H 抑制剂，能显著降低小鼠脑中的 24HC 水平。设计基于 1,3-噁唑的 CYP 抑制剂有望发现对多种 CYP 酶具有显著抑制作用的新型抑制剂。

{"title":"Design and identification of brain-penetrant, potent, and selective 1,3-oxazole-based cholesterol 24-hydroxylase (CH24H) inhibitors","authors":"Yoshiteru Ito , Eiji Kimura , Izumi Nomura , Etsurou Watanabe , Jason Yano , Robert Skene , Maki Miyamoto , Tsuyoshi Ishii , Toshiya Nishi , Tatsuki Koike","doi":"10.1016/j.bmc.2025.118182","DOIUrl":"10.1016/j.bmc.2025.118182","url":null,"abstract":"<div><div>Azole-, pyridine-, and pyrimidine-based cytochrome P450 (CYP) inhibitors strongly bind to CYP enzymes through the coordination between the heme iron of CYP and the sp2-nitrogen atoms of heteroaromatic rings, providing potent pharmacological effects by inhibiting the initiation of the catalytic cycles of target CYP enzymes. Although imidazole-, 1,2,4-triazole-, pyridine-, and pyrimidine-based CYP inhibitors have been widely explored, 1,3-oxazole-based CYP inhibitors have received little attention. In this study, we designed and identified novel 1,3-oxazole-based inhibitors of cholesterol 24- hydroxylase (CH24H; CYP46A1), a brain-specific enzyme involved in cholesterol catabolism, to form 24S-hydroxycholesterol. Detailed insights into the CH24H–ligand interactions were provided by the crystal structures of 1,3-oxazole compounds, including high-throughput screening hit 2 and rationally designed inhibitor 3f. Optimization of 3f led to the identification of 1,3-oxazole derivative 4 l as a potent, selective, and brain-penetrable CH24H inhibitor that significantly reduced 24HC levels in the mouse brain. The design of 1,3-oxazole-based CYP inhibitors holds the potential for the discovery of novel inhibitors with significant potency against a broad spectrum of CYP enzymes.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118182"},"PeriodicalIF":3.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Alchemical free energy-based optimization of quinazoline derivatives as potent EGFR inhibitors with cytotoxic activity

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-04-02 DOI: 10.1016/j.bmc.2025.118179

U. Martínez-Ortega , R. Aguayo-Ortiz , D. Aguilar-Cazares , E.D. Guerrero-Molina , V. Aguilar-Martínez , A. Moreno-Rodríguez , J.S. López-González , J.M. Vázquez-Ramos , F. Hernández-Luis

Gefitinib (GFB) is a well-established EGFR inhibitor used in the treatment of non-small cell lung cancer (NSCLC) that has shown resistance in certain cases of this cancer. In this work, we aimed to enhance GFB’s inhibitory activity using alchemical free energy calculations, leading to the design of five new quinazoline derivatives. Among these, compound 8a was the most potent, inhibiting EGFR at 10 µM and showing significant antiproliferative effects at 25 µM. Further optimization identified two new compounds, NCU00 and NCU01, with improved EGFR inhibition and superior cytotoxicity in four NSCLC cell lines compared to GFB. Molecular dynamics simulations revealed crucial interactions that contribute to the enhanced inhibitory activity of NCU00 and NCU01. Toxicological assessments in mice showed no adverse effects on kidney or liver function, and NCU01 exhibited no developmental toxicity in zebrafish embryos. This study highlights the effectiveness of alchemical free energy methods in optimizing quinazoline-bearing EGFR inhibitors.

{"title":"Alchemical free energy-based optimization of quinazoline derivatives as potent EGFR inhibitors with cytotoxic activity","authors":"U. Martínez-Ortega , R. Aguayo-Ortiz , D. Aguilar-Cazares , E.D. Guerrero-Molina , V. Aguilar-Martínez , A. Moreno-Rodríguez , J.S. López-González , J.M. Vázquez-Ramos , F. Hernández-Luis","doi":"10.1016/j.bmc.2025.118179","DOIUrl":"10.1016/j.bmc.2025.118179","url":null,"abstract":"<div><div>Gefitinib (GFB) is a well-established EGFR inhibitor used in the treatment of non-small cell lung cancer (NSCLC) that has shown resistance in certain cases of this cancer. In this work, we aimed to enhance GFB’s inhibitory activity using alchemical free energy calculations, leading to the design of five new quinazoline derivatives. Among these, compound <strong>8a</strong> was the most potent, inhibiting EGFR at 10 µM and showing significant antiproliferative effects at 25 µM. Further optimization identified two new compounds, <strong>NCU00</strong> and <strong>NCU01</strong>, with improved EGFR inhibition and superior cytotoxicity in four NSCLC cell lines compared to GFB. Molecular dynamics simulations revealed crucial interactions that contribute to the enhanced inhibitory activity of <strong>NCU00</strong> and <strong>NCU01</strong>. Toxicological assessments in mice showed no adverse effects on kidney or liver function, and <strong>NCU01</strong> exhibited no developmental toxicity in zebrafish embryos. This study highlights the effectiveness of alchemical free energy methods in optimizing quinazoline-bearing EGFR inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118179"},"PeriodicalIF":3.3,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Chemical modification of monensin as a source of potent antiplasmodial agents

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-03-30 DOI: 10.1016/j.bmc.2025.118177

Michał Sulik , Eyob A. Workneh , Sofia Santana , Bárbara Teixeira , Miguel Prudêncio , Jan Janczak , Adam Huczyński

Malaria remains a significant public health issue and one of the leading causes of child mortality worldwide. Due to the growing problem of drug resistance, new modes of fighting the disease are searched for. In this context, ionophore antibiotics, natural compounds with high potential for combating parasitic diseases, deserve special attention. The primary representative of such compounds, monensin (MON), demonstrates exceptionally high antiplasmodial activity. In this work, the C26-amino derivative of MON was used as a convenient substrate for the synthesis of its acyl analogues, such as amides and urea. All derivatives exhibited strong activity against the hepatic stage of Plasmodium berghei infection in vitro, which exceeded that shown by the reference drug primaquine. The IC₅₀ value for MON O-phenyl urethane (8) was less than 1 nM.

引用次数: 0

A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-03-29 DOI: 10.1016/j.bmc.2025.118178

Mingyang Liu , Muyan Ke , Hongchen Lu , Ziyu Feng , Kaixuan Wang , Danyang Wang , Kun Wang , Yueping Bai , Song Yang , Lu Miao , Qiang Chen , Mingming Sun , Changliang Shan , Jiancheng Hu , Lingyu Jiang , Hongzhen Jin , Jinfang Hu , Changjiang Huang , Rui Wang , Wei Zhao , Fan Yu

The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth in vitro and in vivo. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound 15a effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound 15a inhibited the proliferation and migration of HepG2 cells, and induced apoptosis in vitro. Furthermore, compound 15a significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound 15a enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.

{"title":"A novel cinnamic acid derivative for hepatocellular carcinoma therapy by degrading METTL16 protein","authors":"Mingyang Liu , Muyan Ke , Hongchen Lu , Ziyu Feng , Kaixuan Wang , Danyang Wang , Kun Wang , Yueping Bai , Song Yang , Lu Miao , Qiang Chen , Mingming Sun , Changliang Shan , Jiancheng Hu , Lingyu Jiang , Hongzhen Jin , Jinfang Hu , Changjiang Huang , Rui Wang , Wei Zhao , Fan Yu","doi":"10.1016/j.bmc.2025.118178","DOIUrl":"10.1016/j.bmc.2025.118178","url":null,"abstract":"<div><div>The RNA methyltransferase methyltransferaselike protein 16 (METTL16) is upregulated in a large proportion of hepatocellular carcinoma (HCC), and its high expression is associated with poor clinical outcomes. METTL16 deletion inhibits HCC growth <em>in vitro</em> and <em>in vivo</em>. Referencing the structure of cinnamic acid, here we designed and synthesized a novel series of small molecular compounds, and found through bioactivity screening that compound <strong>15a</strong> effectively reduced METTL16 level and modulated oncogenic PI3K/AKT pathway signaling. Compound <strong>15a</strong> inhibited the proliferation and migration of HepG2 cells, and induced apoptosis <em>in vitro</em>. Furthermore, compound <strong>15a</strong> significantly inhibited the growth of patient-derived HCC xenografts in nude mice with greater efficacy than the multi-kinase inhibitor lenvatinib. The promising efficacy and good biosafety profile of compound <strong>15a</strong> enables us to further develop this compound for treating patients with HCC and possibly other cancers in clinic.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118178"},"PeriodicalIF":3.3,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Mechanistic study of plasmid DNA delivery by Magainin 2-derived stapled peptides

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-03-26 DOI: 10.1016/j.bmc.2025.118176

Motoharu Hirano , Yuki Takechi-Haraya , Yasuhiro Abe , Takashi Misawa , Norihito Shibata , Yoji Sato , Yosuke Demizu

In this study, the mechanism of the plasmid DNA (pDNA) delivery system using Magainin 2-derived stapled peptides (st7-5 and st7-5_R) was analysed. The effect of different cationic residues (Lys and Arg) on the stability and intracellular transport efficiency of the peptide/pDNA complex was assessed, with both peptides forming stable α-helical structures under neutral conditions and st7-5_R showing higher helical strength under acidic conditions. Agarose gel shift assays and PicoGreen staining showed that both peptides formed complete complexes at N/P ratios of 1.5–2 and protected pDNA from nucleases. However, in the presence of heparin sulfate, the st7-5_R/pDNA complex maintained higher stability than the st7-5/pDNA complex. Interaction analysis with lipid membranes indicated that st7-5 with Lys residues interacted strongly at pH 7.4 and st7-5_R with Arg residues at pH 5.5, suggesting that st7-5_R was highly capable of facilitating its escape from endosomes. The Förster resonance energy transfer (FRET) signal observed by confocal laser scanning microscopy (CLSM) indicated that the st7-5_R/pDNA complex disintegrated over time after intracellular introduction, releasing the encapsulated pDNA into the cell. These results indicate that Magainin 2-derived stapled peptides are promising carriers for efficient intracellular nucleic acid delivery, especially st7-5_R with its excellent stability and delivery efficiency. The findings of this study will contribute to the design of drug delivery system carrier peptides and the improvement of nucleic acid therapeutics.

{"title":"Mechanistic study of plasmid DNA delivery by Magainin 2-derived stapled peptides","authors":"Motoharu Hirano , Yuki Takechi-Haraya , Yasuhiro Abe , Takashi Misawa , Norihito Shibata , Yoji Sato , Yosuke Demizu","doi":"10.1016/j.bmc.2025.118176","DOIUrl":"10.1016/j.bmc.2025.118176","url":null,"abstract":"<div><div>In this study, the mechanism of the plasmid DNA (pDNA) delivery system using Magainin 2-derived stapled peptides (<strong>st7-5</strong> and <strong>st7-5_R</strong>) was analysed. The effect of different cationic residues (Lys and Arg) on the stability and intracellular transport efficiency of the peptide/pDNA complex was assessed, with both peptides forming stable α-helical structures under neutral conditions and <strong>st7-5_R</strong> showing higher helical strength under acidic conditions. Agarose gel shift assays and PicoGreen staining showed that both peptides formed complete complexes at N/P ratios of 1.5–2 and protected pDNA from nucleases. However, in the presence of heparin sulfate, the <strong>st7-5_R</strong>/pDNA complex maintained higher stability than the <strong>st7-5</strong>/pDNA complex. Interaction analysis with lipid membranes indicated that <strong>st7-5</strong> with Lys residues interacted strongly at pH 7.4 and <strong>st7-5_R</strong> with Arg residues at pH 5.5, suggesting that <strong>st7-5_R</strong> was highly capable of facilitating its escape from endosomes. The Förster resonance energy transfer (FRET) signal observed by confocal laser scanning microscopy (CLSM) indicated that the <strong>st7-5_R</strong>/pDNA complex disintegrated over time after intracellular introduction, releasing the encapsulated pDNA into the cell. These results indicate that Magainin 2-derived stapled peptides are promising carriers for efficient intracellular nucleic acid delivery, especially <strong>st7-5_R</strong> with its excellent stability and delivery efficiency. The findings of this study will contribute to the design of drug delivery system carrier peptides and the improvement of nucleic acid therapeutics.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118176"},"PeriodicalIF":3.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143734767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Discovery of novel transforming growth factor β type 1 receptor inhibitors through structure-based virtual screening, preliminary structure–activity relationship study, and biological evaluation in hepatocellular carcinoma

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-03-26 DOI: 10.1016/j.bmc.2025.118175

Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang

The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a pivotal role in the tumor microenvironment, making it an attractive target for therapeutic intervention. Small-molecule inhibitors of TGFβR1 offer a promising approach for the treatment of malignant tumors. In this study, a series of 1H-pyrrolo[2,3-b]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound 7w, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC₅₀ values of 160.3 nM and 228 μM, respectively. Compound 7w showed a synergistic anti-proliferation and pro-apoptotic effect when combined with sorafenib, highlighting its potential as a promising lead for the development of potential anticancer therapies.

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引用次数: 0

Unlocking pH-responsive dual payload release through hydrazone linkage chemistry

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-03-22 DOI: 10.1016/j.bmc.2025.118172

Heba S. Abd-Ellah , Dan Zhao , Yayao Zhou , Jonathan B. Baell

The capacity for simultaneous intracellular delivery of two payloads to various organelles, in a targeted and programmable manner, would represent a powerful tool to probe cellular function and responses or deliver synergistic combination therapies. While only single pathways are currently probed, this work introduces an acid-labile trifunctional hydrazone linker that releases two types of payloads, which we term payload W and payload Z. As a key and controlling feature, initial acid-mediated release of payload W triggers release of payload Z with 1:1 stoichiometry via intramolecular cyclization. An azide group is also built into the linker structure to allow optional conjugation to nanoparticles (NPs). Through overcoming significant synthetic challenges, we have prepared six target acylhydrazone linkers and evaluated their stability over a range of pH values. An acyl acetophenone hydrazone linker (linker 3) displays a particularly promising release profile, supporting the feasibility of the novel dual-release concept through high stability at physiological pH but rapid release of both payloads under pH conditions similar to those in late endosomal and lysosomal compartments (pH 4.5–5.5) or tumor sites (pH 6.5). Therefore, linker 3 holds the potential as an ideal candidate carrier for future nanoparticle conjugation, offering a mechanism for dual drug release after endosomal entrapment. A particularly promising application would be in combination therapy for controlled intracellular delivery of doxorubicin (DOX) and a nitric oxide (NO) donor, or proteins and/or siRNA and small molecules, to enable diverse synergistic treatment strategies.

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引用次数: 0

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