ChemMedChem最新文献

英文中文

Discovery of ICOS‐targeted small molecules using affinity selection mass spectrometry screening 利用亲和选择质谱筛选发现 ICOS 靶向小分子化合物

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-13 DOI: 10.1002/cmdc.202400545

Longfei Zhang, Laura Calvo-Barreiro, Victor de Sousa Batista, Katarzyna Świderek, Moustafa Gabr

Inducible T cell co‐stimulator (ICOS) is a positive immune checkpoint receptor expressed on the surface of activated T cells, which could promote cell function after being stimulated with ICOS ligand (ICOS‐L). Although clinical benefits have been reported in the ICOS modulation‐based treatment for cancer and autoimmune disease, current modulators are restricted in biologics, whereas ICOS‐targeted small molecules are lacking. To fill this gap, we performed an affinity selection mass spectrometry (ASMS) screening for ICOS binding using a library of 15,600 molecules. To the best of our knowledge, this is the first study that utilizes ASMS screening to discover small molecules targeting immune checkpoints. Compound 9 with a promising ICOS/ICOS‐L inhibitory profile (IC50 = 29.38 ± 3.41 µM) was selected as the template for the modification. Following preliminary structure‐activity relationship (SAR) study and molecular dynamic (MD) simulation revealed the critical role of the ortho‐hydroxy group on compound 9 in the ICOS binding, as it could stabilize the interaction via the hydrogen bond formation with residuals on the glycan, and the depletion could lead to an activity lost. This work validates a promising inhibitor for the ICOS/ICOS‐L interaction, and we anticipate future modifications could provide more potent modulators for this interaction.

诱导性 T 细胞协同刺激因子（ICOS）是一种表达在活化 T 细胞表面的阳性免疫检查点受体，在受到 ICOS 配体（ICOS-L）刺激后可促进细胞功能。虽然基于 ICOS 调节治疗癌症和自身免疫性疾病的临床疗效已有报道，但目前的调节剂仅限于生物制剂，而以 ICOS 为靶点的小分子药物却缺乏。为了填补这一空白，我们利用一个包含 15,600 个分子的文库进行了亲和选择质谱（ASMS）筛选，以确定 ICOS 的结合情况。据我们所知，这是第一项利用 ASMS 筛选发现靶向免疫检查点小分子的研究。化合物 9 具有良好的 ICOS/ICOS-L 抑制性（IC50 = 29.38 ± 3.41 µM），被选为改造的模板。初步的结构-活性关系（SAR）研究和分子动力学（MD）模拟揭示了化合物 9 上的正羟基在 ICOS 结合过程中的关键作用，因为它可以通过与聚糖上的残余物形成氢键来稳定相互作用，而氢键的耗竭会导致活性丧失。这项工作验证了 ICOS/ICOS-L 相互作用的一种很有前景的抑制剂，我们预计未来的修饰会为这种相互作用提供更有效的调节剂。

{"title":"Discovery of ICOS‐targeted small molecules using affinity selection mass spectrometry screening","authors":"Longfei Zhang, Laura Calvo-Barreiro, Victor de Sousa Batista, Katarzyna Świderek, Moustafa Gabr","doi":"10.1002/cmdc.202400545","DOIUrl":"https://doi.org/10.1002/cmdc.202400545","url":null,"abstract":"Inducible T cell co‐stimulator (ICOS) is a positive immune checkpoint receptor expressed on the surface of activated T cells, which could promote cell function after being stimulated with ICOS ligand (ICOS‐L). Although clinical benefits have been reported in the ICOS modulation‐based treatment for cancer and autoimmune disease, current modulators are restricted in biologics, whereas ICOS‐targeted small molecules are lacking. To fill this gap, we performed an affinity selection mass spectrometry (ASMS) screening for ICOS binding using a library of 15,600 molecules. To the best of our knowledge, this is the first study that utilizes ASMS screening to discover small molecules targeting immune checkpoints. Compound 9 with a promising ICOS/ICOS‐L inhibitory profile (IC50 = 29.38 ± 3.41 µM) was selected as the template for the modification. Following preliminary structure‐activity relationship (SAR) study and molecular dynamic (MD) simulation revealed the critical role of the ortho‐hydroxy group on compound 9 in the ICOS binding, as it could stabilize the interaction via the hydrogen bond formation with residuals on the glycan, and the depletion could lead to an activity lost. This work validates a promising inhibitor for the ICOS/ICOS‐L interaction, and we anticipate future modifications could provide more potent modulators for this interaction.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142256297","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

Breaking Barriers in Photothermal Tumor Therapy: A Cascade of Strain‐Engineered Nanozyme in Action 打破肿瘤光热疗法的障碍：一连串应变工程纳米酶在发挥作用

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-13 DOI: 10.1002/cmdc.202400443

Srinidhi V. G., Huidrom Mangalsana, Amit Vernekar

Cancer, a deadly and constantly evolving disease, has always been difficult to treat due to the complexity of the tumor microenvironment (TME). Cancer nanomedicines are proving to be a much better alternative for treatment due to their stability and ability to provide an efficient targeted therapy. An amorphous alloy bimetallene with an introduction of 2 % tensile strain with photothermal multiple enzyme‐like catalytic activity is being presented here that functions as a TME‐responsive nanozyme. Labeled as RhRu, this bimetallene, under acidic conditions, functions as oxidase (OXD) – like, peroxidase (POD) – like and catalase (CAT) – like enzymes, by producing radicals and disrupting the tumor cells. This effect is enhanced especially upon irradiation of laser and introduction of tensile strain in its heterophase boundaries. This current highlight discusses the strain engineering tactic of la‐RhRu bimetallene and its potency as an anti‐tumor therapeutic.

癌症是一种致命且不断演变的疾病，由于肿瘤微环境（TME）的复杂性，它一直难以治疗。癌症纳米药物因其稳定性和提供高效靶向治疗的能力而被证明是一种更好的治疗选择。本文介绍了一种非晶合金双茂钛，它引入了 2% 的拉伸应变，具有光热多酶样催化活性，可作为 TME 响应型纳米酶发挥作用。这种被标记为 RhRu 的双金属在酸性条件下可发挥类似氧化酶 (OXD)、过氧化物酶 (POD) 和过氧化氢酶 (CAT) 的功能，产生自由基并破坏肿瘤细胞。特别是在激光照射和在其异相边界引入拉伸应变时，这种效果会得到增强。本报告重点讨论了 la-RhRu 双茂金属的应变工程技术及其作为抗肿瘤疗法的功效。

引用次数: 0

Biomimetic Cell Membrane‐Coated Nanoparticles for Cancer Theranostics 用于癌症血清学的仿生细胞膜包覆纳米粒子

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-12 DOI: 10.1002/cmdc.202400410

Tiantian Jiang, Yiduo Zhan, Jiayao Ding, Zheming Song, Yijing Zhang, Jingchao Li, Ting Su

Nanoparticles can enhance drugs accumulating at the tumor site and hold tremendous promise for achieving effective tumor treatment. However, due to the complexity of cancer heterogeneity and suppressive tumor microenvironment, the delivery of traditional nanoparticles has poor infiltration and off‐target effects, making it difficult to control the drug release rate and causing off‐target toxicity. In recent years, cell membrane‐coated biomimetic nanoparticles have been developed, which have both the natural characteristics of biomembranes and the physical characteristics of traditional nanoparticles, thus improving the homologous targeting ability of nanoparticles to tumor cells and better biocompatibility. In this paper, we reviewed the application of single cell membrane and hybrid cell membrane‐coated biomimetic nanoparticles in the integration for tumor diagnosis and treatment. We talked about the preparation methods of cell membrane‐coated nanoparticles, the targeting mechanisms, and the effects of imaging and therapeutic outcomes of different cell membrane‐coated biomimetic nanoparticles in detail. Finally, we discussed the existing problems and prospects of cell membrane‐coated biomimetic nanomaterials.

纳米颗粒能增强药物在肿瘤部位的蓄积，为实现有效的肿瘤治疗带来巨大希望。然而，由于肿瘤异质性和抑制性肿瘤微环境的复杂性，传统纳米颗粒的给药具有浸润性差、脱靶效应强等特点，导致药物释放速率难以控制，造成脱靶毒性。近年来，细胞膜包覆的仿生物纳米颗粒应运而生，它既具有生物膜的天然特性，又具有传统纳米颗粒的物理特性，从而提高了纳米颗粒对肿瘤细胞的同源靶向能力和更好的生物相容性。本文综述了单细胞膜和混合细胞膜包被生物仿生纳米粒子在肿瘤诊断和治疗一体化中的应用。我们详细介绍了细胞膜包覆纳米粒子的制备方法、靶向机制以及不同细胞膜包覆生物仿生纳米粒子的成像效果和治疗效果。最后，我们讨论了细胞膜包覆仿生纳米材料目前存在的问题和发展前景。

{"title":"Biomimetic Cell Membrane‐Coated Nanoparticles for Cancer Theranostics","authors":"Tiantian Jiang, Yiduo Zhan, Jiayao Ding, Zheming Song, Yijing Zhang, Jingchao Li, Ting Su","doi":"10.1002/cmdc.202400410","DOIUrl":"https://doi.org/10.1002/cmdc.202400410","url":null,"abstract":"Nanoparticles can enhance drugs accumulating at the tumor site and hold tremendous promise for achieving effective tumor treatment. However, due to the complexity of cancer heterogeneity and suppressive tumor microenvironment, the delivery of traditional nanoparticles has poor infiltration and off‐target effects, making it difficult to control the drug release rate and causing off‐target toxicity. In recent years, cell membrane‐coated biomimetic nanoparticles have been developed, which have both the natural characteristics of biomembranes and the physical characteristics of traditional nanoparticles, thus improving the homologous targeting ability of nanoparticles to tumor cells and better biocompatibility. In this paper, we reviewed the application of single cell membrane and hybrid cell membrane‐coated biomimetic nanoparticles in the integration for tumor diagnosis and treatment. We talked about the preparation methods of cell membrane‐coated nanoparticles, the targeting mechanisms, and the effects of imaging and therapeutic outcomes of different cell membrane‐coated biomimetic nanoparticles in detail. Finally, we discussed the existing problems and prospects of cell membrane‐coated biomimetic nanomaterials.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201659","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

Flavonol‐ruthenium complexes as antioxidant and anticancer agents 作为抗氧化剂和抗癌剂的黄酮醇钌复合物

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-12 DOI: 10.1002/cmdc.202400313

Tzenge-Lien Shih, Ting-Wei Wu, Yi-Cheng Chu, Chuan-Hsin Chang, Yu-Hui Hsieh, Mei-Hsin Tang, Pei-Hsuan Hsu, Jih-Jung Chen

Flavonol‐metal complexes can enhance the biological activity of flavonols. Inspired by the potential of ruthenium‐based drugs in pharmaceutical applications, seven flavonol‐Ru (II) complexes were synthesized to evaluate their biological activities. Among these compounds, compounds 8, 11, and 12 showed potent antioxidant activities. Compound 12 exhibited superior anti‐inflammatory activity to natural quercetin, which served as a positive control. This study is the first to report the free radical scavenging abilities and antioxidant activity of flavonol‐Ru (II) complexes. Furthermore, compound 12 demonstrated comparable efficacy to 5‐FU against human non‐small‐cell lung cancer cells (A549). These results strongly support the potential of flavonol‐Ru (II) agents.

黄酮醇-金属配合物可以增强黄酮醇的生物活性。受钌类药物在医药应用中的潜力启发，研究人员合成了七种黄酮醇-钌 (II) 复合物，以评估它们的生物活性。在这些化合物中，化合物 8、11 和 12 具有很强的抗氧化活性。化合物 12 的抗炎活性优于作为阳性对照的天然槲皮素。该研究首次报道了黄酮醇-Ru (II) 复合物清除自由基的能力和抗氧化活性。此外，化合物 12 对人类非小细胞肺癌细胞 (A549) 的疗效与 5-FU 相当。这些结果有力地证明了黄酮醇-Ru (II) 药剂的潜力。

引用次数: 0

Structural basis for inhibition of the SARS‐CoV‐2 nsp16 by substrate‐based dual site inhibitors 基于底物的双位点抑制剂抑制 SARS-CoV-2 nsp16 的结构基础

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-11 DOI: 10.1002/cmdc.202400618

Gints Kalnins, Laura Rudusa, Anna Bula, Diana Zelencova-Gopejenko, Olga Bobileva, Mihails Sisovs, Kaspars Tars, Aigars Jirgensons, Kristaps Jaudzems, Raitis Bobrovs

Coronaviruses, including SARS‐CoV‐2, possess an mRNA 5' capping apparatus capable of mimicking the natural eukaryotic capping signature. Two SAM‐dependent methylating enzymes play important roles in this process: nsp14 methylates the N7 of the guanosine cap, and nsp16‐nsp10 methylates the 2'‐O‐ of subsequent nucleotides of viral mRNA. The 2'‐O‐methylation performed by nsp16‐nsp10 is crucial for the escape of the viral RNA from innate immunity. Inhibition of this enzymatic activity has been proposed as a way to combat coronaviruses. In this study, we employed X‐ray crystallography to analyze the binding of the SAM analogues to the active site of nsp16‐nsp10. We obtained eleven 3D crystal structures of the nsp16‐nsp10 complexes with SAM‐derived inhibitors, demonstrated different conformations of the methionine substituting part of the molecules, and confirmed that simultaneous dual‐site targeting of both SAM and RNA sites correlates with higher inhibitory potential.

包括 SARS-CoV-2 在内的冠状病毒拥有一种 mRNA 5' 带帽装置，能够模仿真核生物的天然带帽特征。两种依赖于 SAM 的甲基化酶在这一过程中发挥了重要作用：nsp14 对鸟苷帽的 N7 进行甲基化，nsp16-nsp10 对病毒 mRNA 随后核苷酸的 2'-O- 进行甲基化。nsp16-nsp10 进行的 2'-O- 甲基化是病毒 RNA 摆脱先天免疫的关键。抑制这种酶的活性被认为是对抗冠状病毒的一种方法。在这项研究中，我们利用 X 射线晶体学分析了 SAM 类似物与 nsp16-nsp10 活性位点的结合。我们获得了 nsp16-nsp10 与 SAM 衍生抑制剂复合物的十一种三维晶体结构，展示了分子中蛋氨酸取代部分的不同构象，并证实了同时靶向 SAM 和 RNA 两个位点具有更高的抑制潜力。

引用次数: 0

Factors Affecting Liquid‐Liquid Phase Separation of RGG Peptides with DNA G‐Quadruplex 影响RGG肽与DNA G-四联体液-液相分离的因素

IF 3.4 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-11 DOI: 10.1002/cmdc.202400460

Daisuke Miyoshi, Sumit Shil, Mitsuki Tsuruta, Keiko Kawauchi

Liquid‐liquid phase separation (LLPS), mediated by G‐quadruplexes (G4s) and intrinsically disordered proteins, particularly those containing RGG domains, plays a critical role in cellular processes and diseases. However, the molecular mechanism and the role of individual amino acid residues of the protein in LLPS with G4 (G4‐LLPS) are still unknown. Here, we systematically designed peptides and investigated the roles of arginine residues in G4‐LLPS. It was found that the FMRP‐derived RGG peptide induced LLPS with G4‐forming Myc‐DNA, whereas a point‐mutated peptide, in which all arginine residues were replaced with lysine, was unable to undergo LLPS, indicating the importance of arginine residues. Moreover, systematically truncated peptides showed that at least five positive net charges of peptide are required to induce G4‐LLPS. Furthermore, quantitative investigation demonstrated that the higher binding affinity of peptides with G4 led to a higher LLPS ability, whereas threshold of the binding affinity for undergoing LLPS was identified. These insights elucidate the pivotal role of arginine in G4‐LLPS and the specific requirement for multiple arginine residues, contributing to a deeper understanding of the complex interplay between intrinsically disordered proteins and nucleic acids.

液-液相分离（LLPS）是由 G-四叠体（G4s）和内在无序蛋白（尤其是含有 RGG 结构域的蛋白）介导的，在细胞过程和疾病中发挥着关键作用。然而，G4 蛋白在 LLPS（G4-LLPS）中的分子机制和单个氨基酸残基的作用仍然未知。在此，我们系统地设计了多肽，并研究了精氨酸残基在 G4-LLPS 中的作用。研究发现，FMRP衍生的RGG多肽能诱导G4形成的Myc-DNA进行LLPS，而所有精氨酸残基都被赖氨酸取代的点突变多肽则不能进行LLPS，这表明了精氨酸残基的重要性。此外，系统截短的多肽表明，诱导 G4-LLPS 至少需要多肽的五个正净电荷。此外，定量研究表明，肽与 G4 的结合亲和力越高，LLPS 能力就越强，同时还确定了发生 LLPS 的结合亲和力阈值。这些发现阐明了精氨酸在 G4-LLPS 中的关键作用以及对多个精氨酸残基的特定要求，有助于加深对内在无序蛋白与核酸之间复杂相互作用的理解。

{"title":"Factors Affecting Liquid‐Liquid Phase Separation of RGG Peptides with DNA G‐Quadruplex","authors":"Daisuke Miyoshi, Sumit Shil, Mitsuki Tsuruta, Keiko Kawauchi","doi":"10.1002/cmdc.202400460","DOIUrl":"https://doi.org/10.1002/cmdc.202400460","url":null,"abstract":"Liquid‐liquid phase separation (LLPS), mediated by G‐quadruplexes (G4s) and intrinsically disordered proteins, particularly those containing RGG domains, plays a critical role in cellular processes and diseases. However, the molecular mechanism and the role of individual amino acid residues of the protein in LLPS with G4 (G4‐LLPS) are still unknown. Here, we systematically designed peptides and investigated the roles of arginine residues in G4‐LLPS. It was found that the FMRP‐derived RGG peptide induced LLPS with G4‐forming Myc‐DNA, whereas a point‐mutated peptide, in which all arginine residues were replaced with lysine, was unable to undergo LLPS, indicating the importance of arginine residues. Moreover, systematically truncated peptides showed that at least five positive net charges of peptide are required to induce G4‐LLPS. Furthermore, quantitative investigation demonstrated that the higher binding affinity of peptides with G4 led to a higher LLPS ability, whereas threshold of the binding affinity for undergoing LLPS was identified. These insights elucidate the pivotal role of arginine in G4‐LLPS and the specific requirement for multiple arginine residues, contributing to a deeper understanding of the complex interplay between intrinsically disordered proteins and nucleic acids.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142201658","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

Phenotypic-based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium Tuberculosis. 基于表型发现和探索具有抗结核分枝杆菌活性的 Resorufin 支架。

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-09 DOI: 10.1002/cmdc.202400482

Eric Tran, Lucy Li, Chen-Yi Cheung, Glen P Carter, Robert W Gable, Nicholas P West, Amandeep Kaur, Yi Sing Gee, Gregory Cook, Jonathan B Baell, Manuela Joerg

Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, a nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb. Complete loss of activity was observed for this compound in Mtb mutants affected in enzyme cofactor F420 biosynthesis (fbiC), suggesting that 1 undergoes prodrug activation in a manner similar to anti-tuberculosis prodrug pretomanid. Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease.

结核病仍然是传染病致死的主要原因。由于结核分枝杆菌（Mtb）的治疗疗程较长，且耐药菌株不断扩散，因此有必要开发新的治疗方案。在表型筛选中，一种硝基呋喃-resorufin 共轭物 1 被鉴定为对全细胞 Mtb 的亚微摩尔强效抑制剂。在受辅助因子 F420 生物合成酶（fbiC）影响的 Mtb 突变体中，观察到该化合物完全丧失活性，这表明 1 的原药活化方式与抗结核原药 pretomanid 相似。通过对结构-活性关系的研究，发现了新型的间苯二酚类似物，它们的抗霉菌活性不依赖于依赖于硝基还原酶（Ddn）的生物活化途径。这些类似物通过另一种目前未知的机制发挥作用，可能会扩大我们治疗这种毁灭性疾病的化学武库，因此很有意义。

{"title":"Phenotypic-based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium Tuberculosis.","authors":"Eric Tran, Lucy Li, Chen-Yi Cheung, Glen P Carter, Robert W Gable, Nicholas P West, Amandeep Kaur, Yi Sing Gee, Gregory Cook, Jonathan B Baell, Manuela Joerg","doi":"10.1002/cmdc.202400482","DOIUrl":"https://doi.org/10.1002/cmdc.202400482","url":null,"abstract":"Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, a nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb. Complete loss of activity was observed for this compound in Mtb mutants affected in enzyme cofactor F420 biosynthesis (fbiC), suggesting that 1 undergoes prodrug activation in a manner similar to anti-tuberculosis prodrug pretomanid. Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152695","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

Cyclodextrin Dimers Functionalized with Biotin as Nanocapsulesfor Active Doxorubicin Delivery against MCF-7 Breast Cell Line. 用生物素功能化的环糊精二聚体作为纳米胶囊，可对 MCF-7 乳腺癌细胞株有效释放多柔比星。

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-09 DOI: 10.1002/cmdc.202400368

Noemi Bognanni, Chiara Scuderi, Valentina Giglio, Fabio Spiteri, Luana La Piana, Daniele Condorelli, Vincenza Barresi, Graziella Vecchio

Cyclodextrin dimers have been investigated as potential nanocapsules of biomolecules. The presence of two cavities can improve the stability of inclusion complexes, working as a hydrophilic sandwich of poorly water-soluble species. Here, we designed new β- and γ-cyclodextrin dimers functionalized with biotin as a targeting unit and tested the new bioconjugates as doxorubicin delivery systems in cancer cells. Biotin can recognize the Sodium-dependent Multivitamin Transporter (SMVT) receptor, encoded by the Solute Carrier Family 5 Member 6 (SLC5A6) gene and improve the uptake of drugs. We evaluated the expression of the SLC5A6 transcript in human cell lines to select the best cell model (MCF-7) for the in vitro studies. Furthermore, in the cell lines, we investigated the transcript levels of genes correlated to biotin cell availability, Holocarboxylase Synthetase (or HCS encoded by HLCS gene) and Biotinidase (encoded by BTD gene) enzymes. Moreover, the expression of ATP Binding Cassette Subfamily G Member 2 transporter (encoded by ABCG2 gene), which may play a role in doxorubicin resistance, has been investigated. The antiproliferative activity of the doxorubicin complexes with the dimers has been determined to study the effect of the biotin moiety on the cytotoxicity in MCF-7 cancer cells.

环糊精二聚体被研究用作潜在的生物分子纳米胶囊。两个空腔的存在可以提高包合物的稳定性，成为水溶性差的物种的亲水夹层。在这里，我们设计了以生物素为靶向单元的新型β-和γ-环糊精二聚体，并将这种新型生物共轭物作为多柔比星递送系统在癌细胞中进行了测试。生物素可以识别由溶质运载家族 5 号成员 6（SLC5A6）基因编码的钠依赖性多维生素转运体（SMVT）受体，从而提高药物的吸收。我们评估了 SLC5A6 转录本在人类细胞系中的表达情况，选择了最佳细胞模型（MCF-7）进行体外研究。此外，我们还研究了细胞系中与生物素细胞可用性相关的基因、全羧化酶合成酶（或由 HLCS 基因编码的 HCS）和生物素酶（由 BTD 基因编码）的转录水平。此外，还研究了可能在多柔比星耐药性中发挥作用的 ATP 结合盒式 G 亚家族成员 2 转运体（由 ABCG2 基因编码）的表达情况。测定了多柔比星与二聚体复合物的抗增殖活性，以研究生物素分子对 MCF-7 癌细胞细胞毒性的影响。

{"title":"Cyclodextrin Dimers Functionalized with Biotin as Nanocapsulesfor Active Doxorubicin Delivery against MCF-7 Breast Cell Line.","authors":"Noemi Bognanni, Chiara Scuderi, Valentina Giglio, Fabio Spiteri, Luana La Piana, Daniele Condorelli, Vincenza Barresi, Graziella Vecchio","doi":"10.1002/cmdc.202400368","DOIUrl":"https://doi.org/10.1002/cmdc.202400368","url":null,"abstract":"Cyclodextrin dimers have been investigated as potential nanocapsules of biomolecules. The presence of two cavities can improve the stability of inclusion complexes, working as a hydrophilic sandwich of poorly water-soluble species. Here, we designed new β- and γ-cyclodextrin dimers functionalized with biotin as a targeting unit and tested the new bioconjugates as doxorubicin delivery systems in cancer cells. Biotin can recognize the Sodium-dependent Multivitamin Transporter (SMVT) receptor, encoded by the Solute Carrier Family 5 Member 6 (SLC5A6) gene and improve the uptake of drugs. We evaluated the expression of the SLC5A6 transcript in human cell lines to select the best cell model (MCF-7) for the in vitro studies. Furthermore, in the cell lines, we investigated the transcript levels of genes correlated to biotin cell availability, Holocarboxylase Synthetase (or HCS encoded by HLCS gene) and Biotinidase (encoded by BTD gene) enzymes. Moreover, the expression of ATP Binding Cassette Subfamily G Member 2 transporter (encoded by ABCG2 gene), which may play a role in doxorubicin resistance, has been investigated. The antiproliferative activity of the doxorubicin complexes with the dimers has been determined to study the effect of the biotin moiety on the cytotoxicity in MCF-7 cancer cells.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142152693","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

Development of Integrin Targeting Chimeras (ITACs) for the Lysosomal Degradation of Extracellular Proteins. 开发用于细胞外蛋白质溶酶体降解的整合素靶向嵌合体 (ITAC)。

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-08 DOI: 10.1002/cmdc.202300643

Yaxian Zhou, Yaxian Liao, Yuan Zhao, Weiping Tang

The emerging of lysosomal targeting chimera (LYTAC) expands the field of targeted protein degradation (TPD) to include the extracellular proteins for precise depletion. However, most of the reported LYTACs either induce ubiquitous degradation of the protein of interest (POI) in a broad range of tissues or specifically target liver cells. More tissue-selective degraders are highly desirable. Herein, we describe the development of cyclic RGD (cRGD) peptide-antibody conjugates as a novel class of integrin targeting chimeras (ITACs) with potential cancer selectivity. Our results indicate that the ITACs are able to recruit integrin to induce the degradation of both soluble and membrane targets in the lysosome. We observed higher efficiency of ITACs on degrading membrane protein in cancer cells, providing a promising platform for cancer-selective TPD strategy.

溶酶体靶向嵌合体（LYTAC）的出现扩大了靶向蛋白质降解（TPD）的领域，将细胞外蛋白质也包括在内，以实现精确降解。然而，大多数已报道的 LYTAC 要么能在广泛的组织中诱导相关蛋白（POI）的普遍降解，要么能特异性地靶向肝细胞。我们非常需要更具组织选择性的降解剂。在此，我们介绍了环RGD（cRGD）肽-抗体共轭物的开发情况，这是一类新型整合素靶向嵌合体（ITACs），具有潜在的癌症选择性。我们的研究结果表明，ITACs 能够招募整合素，诱导溶酶体中可溶性和膜靶标的降解。我们观察到 ITACs 降解癌细胞膜蛋白的效率更高，为癌症选择性 TPD 策略提供了一个前景广阔的平台。

引用次数: 0

Enhancing Flucytosine Anticandidal Activity Using PEGylated Squalene Nanocarrier. 利用聚乙二醇化角鲨烯纳米载体增强氟西多辛的抗念珠菌活性

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem

Pub Date : 2024-09-06 DOI: 10.1002/cmdc.202400432

Bogdan Florin Craciun, Irina Rosca, Dragos Peptanariu, Mariana Pinteala

There is an emerging necessity for improved therapies against Candida-related infections, with significant implications for global healthcare. Current antifungal agents, limited in number, target specific pathways, but resistance remains a concern. Flucytosine (5FC) exhibits antifungal activity, particularly against Candida. However, monotherapy efficacy is limited, necessitating combination treatments. Herein, we report PEGylated squalene-based nanocarriers for 5FC loading, aiming to enhance its monotherapy efficacy against Candida strains. The loading of 5FC within micelles was achieved using the ultrasound-assisted solvent evaporation method. The 5FC-loaded micelles, together with non-loaded micelles, were thoroughly characterized and analyzed. STEM and DLS analysis confirmed the core-shell morphology with nanometric dimensions along with improved colloidal stability. The quantification of drug loading efficiency and drug loading capacity was calculated using the UV-Vis technique. The in vitro drug-release studies in simulated physiological conditions showed sustained release within 48 hours. Moreover, the release kinetics calculated using mathematical models showed a Fickian diffusion drug release mechanism in simulated physiological conditions with a slower diffusion rate. The in vitro antifungal activity was tested on Candida albicans, Candida glabrata, and Candida parapsilosis. The results showed improved antifungal activity for the nanotherapeutic and unchanged in vitro toxicity toward normal cells, suggesting promising advancements in 5FC therapy.

针对念珠菌相关感染改进疗法的必要性日益凸显，这对全球医疗保健产生了重大影响。目前的抗真菌药物数量有限，主要针对特定途径，但耐药性仍然是一个令人担忧的问题。氟胞嘧啶（5FC）具有抗真菌活性，特别是对念珠菌。然而，单一疗法的疗效有限，因此需要联合疗法。在此，我们报告了用于装载 5FC 的 PEG 化角鲨烷基纳米载体，旨在提高其对念珠菌菌株的单药疗效。5FC在胶束中的负载是通过超声辅助溶剂蒸发法实现的。对载入 5FC 的胶束和未载入 5FC 的胶束进行了全面的表征和分析。STEM 和 DLS 分析证实了具有纳米尺寸的核壳形态，同时提高了胶体稳定性。利用紫外可见光技术计算了药物负载效率和药物负载能力。模拟生理条件下的体外药物释放研究表明，药物可在 48 小时内持续释放。此外，利用数学模型计算的释放动力学表明，在模拟生理条件下，药物释放机制为菲氏扩散，扩散速度较慢。对白色念珠菌、光滑念珠菌和副丝状念珠菌进行了体外抗真菌活性测试。结果表明，该纳米疗法的抗真菌活性有所提高，而对正常细胞的体外毒性不变，这表明 5FC 疗法有望取得进展。

{"title":"Enhancing Flucytosine Anticandidal Activity Using PEGylated Squalene Nanocarrier.","authors":"Bogdan Florin Craciun, Irina Rosca, Dragos Peptanariu, Mariana Pinteala","doi":"10.1002/cmdc.202400432","DOIUrl":"https://doi.org/10.1002/cmdc.202400432","url":null,"abstract":"There is an emerging necessity for improved therapies against Candida-related infections, with significant implications for global healthcare. Current antifungal agents, limited in number, target specific pathways, but resistance remains a concern. Flucytosine (5FC) exhibits antifungal activity, particularly against Candida. However, monotherapy efficacy is limited, necessitating combination treatments. Herein, we report PEGylated squalene-based nanocarriers for 5FC loading, aiming to enhance its monotherapy efficacy against Candida strains. The loading of 5FC within micelles was achieved using the ultrasound-assisted solvent evaporation method. The 5FC-loaded micelles, together with non-loaded micelles, were thoroughly characterized and analyzed. STEM and DLS analysis confirmed the core-shell morphology with nanometric dimensions along with improved colloidal stability. The quantification of drug loading efficiency and drug loading capacity was calculated using the UV-Vis technique. The in vitro drug-release studies in simulated physiological conditions showed sustained release within 48 hours. Moreover, the release kinetics calculated using mathematical models showed a Fickian diffusion drug release mechanism in simulated physiological conditions with a slower diffusion rate. The in vitro antifungal activity was tested on Candida albicans, Candida glabrata, and Candida parapsilosis. The results showed improved antifungal activity for the nanotherapeutic and unchanged in vitro toxicity toward normal cells, suggesting promising advancements in 5FC therapy.","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138756","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

首页上一页

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

ChemMedChem

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀