靶向导致遗传性 ALS/FTD 的 RNA 重复扩展的小分子的结构特征。
Structural Features of Small Molecules Targeting the RNA Repeat Expansion That Causes Genetically Defined ALS/FTD.
机构信息
Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
Department of Chemistry and Biochemistry, Florida Atlantic University, Jupiter, Florida 33458, United States.
出版信息
ACS Chem Biol. 2020 Dec 18;15(12):3112-3123. doi: 10.1021/acschembio.0c00049. Epub 2020 Nov 16.
Abstract
Genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively named c9ALS/FTD, are triggered by hexanucleotide GGGGCC repeat expansions [r(GC)] within the gene. In these diseases, neuronal loss occurs through an interplay of deleterious phenotypes, including r(GC) RNA gain-of-function mechanisms. Herein, we identified a benzimidazole derivative, CB096, that specifically binds to a repeating 1 × 1 GG internal loop structure, 5'CG/3'GC, that is formed when r(GC) folds. Structure-activity relationship (SAR) studies and molecular dynamics (MD) simulations were used to define the molecular interactions formed between CB096 and r(GC) that results in the rescue of disease-associated pathways. Overall, this study reveals a unique structural feature within r(GC) that can be exploited for the development of lead medicines and chemical probes.
摘要
基因定义的肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD），统称为 c9ALS/FTD，是由 基因内六核苷酸 GGGGCC 重复扩展 [r(GC)]触发的。在这些疾病中，神经元的丧失是通过有害表型的相互作用发生的，包括 r(GC) RNA 获得功能机制。在此，我们鉴定了一种苯并咪唑衍生物 CB096，它特异性地结合到 r(GC) 折叠时形成的重复 1×1 GG 内部环结构 5'CG/3'GC。通过构效关系（SAR）研究和分子动力学（MD）模拟来定义 CB096 和 r(GC) 之间形成的分子相互作用，这些相互作用导致与疾病相关的途径得到挽救。总的来说，这项研究揭示了 r(GC) 内的一个独特结构特征，可用于开发先导药物和化学探针。
相似文献
1
Structural Features of Small Molecules Targeting the RNA Repeat Expansion That Causes Genetically Defined ALS/FTD.靶向导致遗传性 ALS/FTD 的 RNA 重复扩展的小分子的结构特征。
ACS Chem Biol. 2020 Dec 18;15(12):3112-3123. doi: 10.1021/acschembio.0c00049. Epub 2020 Nov 16.
2
A Small Molecule Exploits Hidden Structural Features within the RNA Repeat Expansion That Causes c9ALS/FTD and Rescues Pathological Hallmarks.小分子利用导致 c9ALS/FTD 的 RNA 重复扩展中的隐藏结构特征，并挽救病理特征。
ACS Chem Neurosci. 2021 Nov 3;12(21):4076-4089. doi: 10.1021/acschemneuro.1c00470. Epub 2021 Oct 22.
3
The Hairpin Form of r(GC) in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules.c9ALS/FTD 中 r(GC)的发夹结构是重复相关的非 ATG 翻译产物，也是生物活性小分子的作用靶点。
Cell Chem Biol. 2019 Feb 21;26(2):179-190.e12. doi: 10.1016/j.chembiol.2018.10.018. Epub 2018 Nov 29.
4
Conformational dynamics of RNA G4C2 and G2C4 repeat expansions causing ALS/FTD using NMR and molecular dynamics studies.使用 NMR 和分子动力学研究导致 ALS/FTD 的 RNA G4C2 和 G2C4 重复扩展的构象动力学。
Nucleic Acids Res. 2023 Jun 23;51(11):5325-5340. doi: 10.1093/nar/gkad403.
5
G-quadruplex-binding small molecules ameliorate FTD/ALS pathology and .G-四链体结合小分子改善 FTD/ALS 病理学和 。
EMBO Mol Med. 2018 Jan;10(1):22-31. doi: 10.15252/emmm.201707850.
6
Structural insight into C9orf72 hexanucleotide repeat expansions: Towards new therapeutic targets in FTD-ALS.对C9orf72六核苷酸重复序列扩增的结构洞察：迈向额颞叶痴呆-肌萎缩侧索硬化症的新治疗靶点
Neurochem Int. 2016 Nov;100:11-20. doi: 10.1016/j.neuint.2016.08.008. Epub 2016 Aug 15.
7
Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(GC) repeat expansion in vitro and in vivo ALS models.利用小分子招募核糖核酸酶，减少体外和体内 ALS 模型中 c9ALS/FTD r(GC) 重复扩展。
Sci Transl Med. 2021 Oct 27;13(617):eabd5991. doi: 10.1126/scitranslmed.abd5991.
8
Crystal structure of parallel G-quadruplex formed by the two-repeat ALS- and FTD-related GGGGCC sequence.两重复制 ALS 和 FTD 相关 GGGGCC 序列形成的平行 G-四链体的晶体结构。
Nucleic Acids Res. 2021 Jun 4;49(10):5881-5890. doi: 10.1093/nar/gkab302.
9
Crystal structure of a tetrameric RNA G-quadruplex formed by hexanucleotide repeat expansions of C9orf72 in ALS/FTD.ALS/FTD 中 C9orf72 六核苷酸重复扩增形成的四聚体 RNA G-四链体的晶体结构。
Nucleic Acids Res. 2024 Jul 22;52(13):7961-7970. doi: 10.1093/nar/gkae473.
10
Topology of a G-quadruplex DNA formed by C9orf72 hexanucleotide repeats associated with ALS and FTD.由与肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）相关的C9orf72六核苷酸重复序列形成的G-四链体DNA的拓扑结构。
Sci Rep. 2015 Nov 13;5:16673. doi: 10.1038/srep16673.
引用本文的文献
1
Experimental and computational investigations of RNA duplexes containing N7-regioisomers of adenosine and LNA-adenosine.含腺苷N7-区域异构体和锁核酸-腺苷的RNA双链体的实验与计算研究
Nucleic Acids Res. 2025 Jan 7;53(1). doi: 10.1093/nar/gkae1222.
2
Antisense RNA C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms a triplex-like structure and binds small synthetic ligand.C9orf72 反义 RNA 六核苷酸重复与肌萎缩侧索硬化症和额颞叶痴呆相关，形成三链体样结构并结合小分子合成配体。
Nucleic Acids Res. 2024 Jun 24;52(11):6707-6717. doi: 10.1093/nar/gkae376.
3
Advances in the Structure of GGGGCC Repeat RNA Sequence and Its Interaction with Small Molecules and Protein Partners.GGGGGCC 重复 RNA 序列结构及其与小分子和蛋白质伴侣相互作用的研究进展。
Molecules. 2023 Aug 1;28(15):5801. doi: 10.3390/molecules28155801.
4
Small molecules targeting different cellular pathologies for the treatment of amyotrophic lateral sclerosis.针对肌萎缩侧索硬化症不同细胞病理学的小分子治疗药物。
Med Res Rev. 2023 Nov;43(6):2260-2302. doi: 10.1002/med.21974. Epub 2023 May 26.
5
Dynamic docking of small molecules targeting RNA CUG repeats causing myotonic dystrophy type 1.靶向 RNA CUG 重复序列导致 1 型肌强直性营养不良的小分子的动态对接。
Biophys J. 2023 Jan 3;122(1):180-196. doi: 10.1016/j.bpj.2022.11.010. Epub 2022 Nov 8.
6
Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(GC) repeat expansion in vitro and in vivo ALS models.利用小分子招募核糖核酸酶，减少体外和体内 ALS 模型中 c9ALS/FTD r(GC) 重复扩展。
Sci Transl Med. 2021 Oct 27;13(617):eabd5991. doi: 10.1126/scitranslmed.abd5991.
7
A Small Molecule Exploits Hidden Structural Features within the RNA Repeat Expansion That Causes c9ALS/FTD and Rescues Pathological Hallmarks.小分子利用导致 c9ALS/FTD 的 RNA 重复扩展中的隐藏结构特征，并挽救病理特征。
ACS Chem Neurosci. 2021 Nov 3;12(21):4076-4089. doi: 10.1021/acschemneuro.1c00470. Epub 2021 Oct 22.
8
Supramolecular Polymorphism of (GC) Repeats Associated with ALS and FTD.（GC）重复相关的 ALS 和额颞叶痴呆的超分子多态性。
Int J Mol Sci. 2021 Apr 26;22(9):4532. doi: 10.3390/ijms22094532.
9
Targeting the ALS/FTD-associated A-DNA kink with anthracene-based metal complex causes DNA backbone straightening and groove contraction.靶向 ALS/FTD 相关的 A-DNA 扭结的蒽基金属配合物导致 DNA 骨架变直和沟槽收缩。
Nucleic Acids Res. 2021 Sep 20;49(16):9526-9538. doi: 10.1093/nar/gkab227.
本文引用的文献
1
Small-molecule targeted recruitment of a nuclease to cleave an oncogenic RNA in a mouse model of metastatic cancer.小分子靶向招募核酸酶在转移性癌症的小鼠模型中切割致癌 RNA。
Proc Natl Acad Sci U S A. 2020 Feb 4;117(5):2406-2411. doi: 10.1073/pnas.1914286117. Epub 2020 Jan 21.
2
Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.患者定制型寡核苷酸疗法治疗罕见遗传病。
N Engl J Med. 2019 Oct 24;381(17):1644-1652. doi: 10.1056/NEJMoa1813279. Epub 2019 Oct 9.
3
π-Hole Interactions Involving Nitro Aromatic Ligands in Protein Structures.π-hole 相互作用涉及蛋白质结构中的硝基芳基配体。
Chemistry. 2019 Oct 17;25(58):13436-13443. doi: 10.1002/chem.201903404. Epub 2019 Sep 17.
4
C9orf72 and triplet repeat disorder RNAs: G-quadruplex formation, binding to PRC2 and implications for disease mechanisms.C9orf72 和三核苷酸重复障碍 RNA：G-四链体形成、与 PRC2 的结合及其对疾病机制的影响。
RNA. 2019 Aug;25(8):935-947. doi: 10.1261/rna.071191.119. Epub 2019 May 2.
5
Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy.与 C9orf72 相关的 TDP-43 蛋白病变相关的应激颗粒驻留蛋白的异常沉积。
Mol Neurodegener. 2019 Feb 15;14(1):9. doi: 10.1186/s13024-019-0310-z.
6
Targeting RNA: A Transformative Therapeutic Strategy.靶向 RNA：一种变革性的治疗策略。
Clin Transl Sci. 2019 Mar;12(2):98-112. doi: 10.1111/cts.12624. Epub 2019 Feb 27.
7
The Hairpin Form of r(GC) in c9ALS/FTD Is Repeat-Associated Non-ATG Translated and a Target for Bioactive Small Molecules.c9ALS/FTD 中 r(GC)的发夹结构是重复相关的非 ATG 翻译产物，也是生物活性小分子的作用靶点。
Cell Chem Biol. 2019 Feb 21;26(2):179-190.e12. doi: 10.1016/j.chembiol.2018.10.018. Epub 2018 Nov 29.
8
C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies.C9orf72-FTD/ALS 发病机制：来自人类神经病理学研究的证据。
Acta Neuropathol. 2019 Jan;137(1):1-26. doi: 10.1007/s00401-018-1921-0. Epub 2018 Oct 27.
9
C9orf72-mediated ALS and FTD: multiple pathways to disease.C9orf72 介导的肌萎缩侧索硬化症和额颞叶痴呆：多种疾病途径。
Nat Rev Neurol. 2018 Sep;14(9):544-558. doi: 10.1038/s41582-018-0047-2.
10
Selective Small Molecule Recognition of RNA Base Pairs.选择性小分子识别 RNA 碱基对。
ACS Comb Sci. 2018 Aug 13;20(8):482-491. doi: 10.1021/acscombsci.8b00049. Epub 2018 Jul 31.
Zotero 插件