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Targeting SHP2 with an Active Site Inhibitor Blocks Signaling and Breast Cancer Cell Phenotypes 用活性位点抑制剂靶向SHP2阻断信号传导和乳腺癌细胞表型
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-07-14 DOI: 10.1021/acsbiomedchemau.3c00024
Dhanaji M. Lade,  and , Yehenew M. Agazie*, 

The Src homology phosphotyrosyl phosphatase 2 (SHP2) is an oncogenic protein for which targeted therapies are being sought. In line with this idea, we have previously reported the development of a specific active site inhibitor named CNBDA that showed effectivity in suppressing the transformation phenotypes of breast cancer cells. To improve efficacy, we introduced limited modifications to the parent compound and tested potency in vitro and under cell culture conditions. Of these modifications, removal of one of the butyric acid groups led to the production of a compound named CNBCA, which showed a 5.7-fold better potency against the SHP2 enzyme activity in vitro. In addition, CNBCA showed better selectivity to SHP2 than the control PTPs (SHP1 and PTP1B) as determined by the phosphatase assay. Furthermore, CNBCA binds and inhibits enzyme activity of full-length SHP2 in cellular contexts, downregulates SHP2 mediated signaling, and suppresses breast cancer cell phenotypes, including cell proliferation, colony formation, and mammosphere growth. These findings show that targeting SHP2 with CNBCA is effective against the cancerous properties of breast cancer cells.

Src同源磷酸酪氨酸磷酸酶2(SHP2)是一种正在寻求靶向治疗的致癌蛋白。根据这一想法,我们之前报道了一种名为CNBDA的特异性活性位点抑制剂的开发,该抑制剂在抑制癌症细胞的转化表型方面表现出有效性。为了提高效力,我们对母体化合物进行了有限的修饰,并在体外和细胞培养条件下测试了效力。在这些修饰中,去除一个丁酸基团导致产生了一种名为CNBCA的化合物,该化合物在体外对SHP2酶活性的效力提高了5.7倍。此外,通过磷酸酶测定测定,CNBCA对SHP2表现出比对照PTP(SHP1和PTP1B)更好的选择性。此外,CNBCA在细胞环境中结合并抑制全长SHP2的酶活性,下调SHP2介导的信号传导,并抑制乳腺癌症细胞表型,包括细胞增殖、集落形成和乳腺球生长。这些发现表明,用CNBCA靶向SHP2对乳腺癌症细胞的癌性是有效的。
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引用次数: 0
Cytochromes P450 Associated with the Biosyntheses of Ribosomally Synthesized and Post-translationally Modified Peptides 细胞色素P450与核糖体合成和翻译后修饰肽的生物合成有关
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-07-13 DOI: 10.1021/acsbiomedchemau.3c00026
Guannan Zhong*, 

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a class of exponentially increased natural products with characteristic chemical structures, topologies, and biosynthetic mechanisms as well as exceptional bioactivities including antibacteria, antitumors, and antiviruses. The biosynthesis of RiPP proceeds via a ribosomally assembled precursor peptide that undergoes varied post-translational modifications to generate a mature peptide. Cytochrome P450 (CYP or P450) monooxygenases are a superfamily of heme-containing enzymes that span a wide range of secondary metabolite biosynthetic pathways due to their broad substrate scopes and excellent catalytic versatility. In contrast to the enormous quantities of RiPPs and P450s, the P450 associated RiPP biosynthesis is comparatively limited, with most of their functions and timings remaining mysterious. Herein, this Review aims to provide an overview on the striking roles of P450s in RiPP biosyntheses uncovered to date and to illustrate their remarkable functions, mechanisms, as well as remaining challenges. This will shed light on novel P450 discovery and characterizations in RiPP biosyntheses.

核糖体合成和翻译后修饰肽(RiPP)是一类呈指数增长的天然产物,具有独特的化学结构、拓扑结构和生物合成机制,以及特殊的生物活性,包括抗菌、抗肿瘤和抗病毒。RiPP的生物合成通过核糖体组装的前体肽进行,该前体肽经历各种翻译后修饰以产生成熟肽。细胞色素P450(CYP或P450)单加氧酶是一个含血红素酶的超家族,由于其广泛的底物范围和优异的催化多功能性,它跨越了广泛的次级代谢产物生物合成途径。与大量的RiPP和P450形成对比的是,与P450相关的RiPP生物合成相对有限,它们的大部分功能和时间仍然神秘。在此,本综述旨在概述P450在迄今为止发现的RiPP生物合成中的显著作用,并说明其显著的功能、机制以及剩余的挑战。这将有助于阐明新的P450发现和RiPP生物合成中的特征。
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引用次数: 1
Hydrogen Sulfide Responsive Phototherapy Agents: Design Strategies and Biological Applications 硫化氢反应性光治疗剂:设计策略和生物学应用
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-06-23 DOI: 10.1021/acsbiomedchemau.3c00028
Musa Dirak, Sarp E. Turan and Safacan Kolemen*, 

Hydrogen sulfide (H2S) is one of the critical gasotransmitters, which play important roles in regular physiological processes, especially in vital signaling pathways. However, fluctuations in endogenous H2S concentration can be linked to serious health problems, such as neurodegenerative diseases, cancer, diabetes, inflammation, cardiovascular diseases, and hypertension. Thus, it has attracted a great deal of attention in therapeutic applications, specifically in the field of phototherapy. Photodynamic therapy (PDT) and photothermal therapy (PTT) are two subclasses of phototherapy, which utilize either reactive oxygen species (ROS) or local temperature increase upon irradiation of a photosensitizer (PS) to realize the therapeutic action. Phototherapies offer unique advantages compared to conventional methods; thus, they are highly promising and popular. One of the design principles followed in new generation PSs is to build activity-based PSs, which stay inactive before getting activated by disease-associated stimuli. These activatable PSs dramatically improve the selectivity and efficacy of the therapy. In this review, we summarize small molecule and nanomaterial-based PDT and PTT agents that are activated selectively by H2S to initiate their cytotoxic effect. We incorporate single mode PDT and PTT agents along with synergistic and/or multimodal photosensitizers that can combine more than one therapeutic approach. Additionally, H2S-responsive theranostic agents, which offer therapy and imaging at the same time, are highlighted. Design approaches, working principles, and biological applications for each example are discussed in detail.

硫化氢(H2S)是一种重要的气体递质,在正常的生理过程中发挥着重要作用,尤其是在重要的信号通路中。然而,内源性H2S浓度的波动可能与严重的健康问题有关,如神经退行性疾病、癌症、糖尿病、炎症、心血管疾病和高血压。因此,它在治疗应用中,特别是在光疗领域引起了极大的关注。光动力疗法(PDT)和光热疗法(PTT)是光疗的两个亚类,它们利用活性氧(ROS)或光敏剂(PS)照射后的局部温度升高来实现治疗作用。与传统方法相比,光疗法具有独特的优势;因此,它们非常有前途和受欢迎。新一代PS遵循的设计原则之一是构建基于活动的PS,它在被疾病相关刺激激活之前保持不活动状态。这些可激活的PS显著提高了治疗的选择性和疗效。在这篇综述中,我们总结了基于小分子和纳米材料的PDT和PTT试剂,它们被H2S选择性激活以启动其细胞毒性作用。我们结合了单模PDT和PTT药物,以及可以结合多种治疗方法的协同和/或多模式光敏剂。此外,强调了同时提供治疗和成像的H2S反应性治疗剂。详细讨论了每个例子的设计方法、工作原理和生物学应用。
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引用次数: 0
Structure-Based Design of Inhibitors of the m6A-RNA Writer Enzyme METTL3 m6A-RNA写入酶METTL3抑制剂的结构设计
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-06-14 DOI: 10.1021/acsbiomedchemau.3c00023
Rajiv Kumar Bedi, Danzhi Huang, Yaozong Li and Amedeo Caflisch*, 

Methyltransferase-like 3 (METTL3) and METTL14 form a heterodimeric complex that catalyzes the most abundant internal mRNA modification, N6-methyladenosine (m6A). METTL3 is the catalytic subunit that binds the co-substrate S-adenosyl methionine (SAM), while METTL14 is involved in mRNA binding. The m6A modification provides post-transcriptional level control over gene expression as it affects almost all stages of the mRNA life cycle, including splicing, nuclear export, translation, and decay. There is increasing evidence for an oncogenic role of METTL3 in acute myeloid leukemia. Here, we use structural and dynamic details of the catalytic subunit METTL3 for developing small-molecule inhibitors that compete with SAM. Starting from a hit identified by high-throughput docking, protein crystallography and molecular dynamics simulations were employed to guide the optimization of inhibitory activity. The potency was successfully improved by 8000-fold as measured by a homogeneous time-resolved fluorescence assay. The optimized compound is selective against the off-targets RNA methyltransferases METTL1 and METTL16.

甲基转移酶样3(METTL3)和METTL14形成异二聚体复合物,催化最丰富的内部信使核糖核酸修饰N6-甲基腺苷(m6A)。METTL3是结合共底物S-腺苷甲硫氨酸(SAM)的催化亚基,而METTL14参与mRNA结合。m6A修饰提供了对基因表达的转录后水平控制,因为它几乎影响mRNA生命周期的所有阶段,包括剪接、核输出、翻译和衰变。越来越多的证据表明METTL3在急性髓系白血病中具有致癌作用。在这里,我们使用催化亚基METTL3的结构和动力学细节来开发与SAM竞争的小分子抑制剂。从高通量对接确定的命中开始,蛋白质晶体学和分子动力学模拟被用于指导抑制活性的优化。通过均匀时间分辨荧光测定法测量,效价成功地提高了8000倍。优化的化合物对脱靶RNA甲基转移酶METTL1和METTL16具有选择性。
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引用次数: 1
Chemical Tools to Image the Activity of PAR-Cleaving Proteases 化学工具成像par切割蛋白酶的活性
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-05-27 DOI: 10.1021/acsbiomedchemau.3c00019
Irene Y. Lee, Piyapa Tantisirivat and Laura E. Edgington-Mitchell*, 

Protease-activated receptors (PARs) comprise a family of four G protein-coupled receptors (GPCRs) that have broad functions in health and disease. Unlike most GPCRs, PARs are uniquely activated by proteolytic cleavage of their extracellular N termini. To fully understand PAR activation and function in vivo, it is critical to also study the proteases that activate them. As proteases are heavily regulated at the post-translational level, measures of total protease abundance have limited utility. Measures of protease activity are instead required to inform their function. This review will introduce several classes of chemical probes that have been developed to measure the activation of PAR-cleaving proteases. Their strengths, weaknesses, and applications will be discussed, especially as applied to image protease activity at the whole organism, tissue, and cellular level.

蛋白酶激活受体(PAR)包括一个由四个G蛋白偶联受体(GPCR)组成的家族,在健康和疾病中具有广泛的功能。与大多数GPCR不同,PAR通过蛋白水解裂解其细胞外N末端而被独特激活。为了充分了解标准杆数在体内的激活和功能,研究激活它们的蛋白酶也是至关重要的。由于蛋白酶在翻译后水平上受到严重调节,因此总蛋白酶丰度的测量作用有限。相反,需要蛋白酶活性的测量来告知它们的功能。这篇综述将介绍几类化学探针,这些探针已被开发用于测量PAR-离去蛋白酶的激活。将讨论它们的优点、缺点和应用,特别是应用于整个生物体、组织和细胞水平的图像蛋白酶活性。
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引用次数: 0
Multiplex Protein Imaging through PACIFIC: Photoactive Immunofluorescence with Iterative Cleavage 多重蛋白成像通过太平洋:光活性免疫荧光与迭代切割
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-04-28 DOI: 10.1021/acsbiomedchemau.3c00018
Fei Ji, Moises Hur, Sungwon Hur, Siwen Wang, Priyanka Sarkar, Shiqun Shao, Desiree Aispuro, Xu Cong, Yanhao Hu, Zhonghan Li* and Min Xue*, 

Multiplex protein imaging technologies enable deep phenotyping and provide rich spatial information about biological samples. Existing methods have shown great success but also harbored trade-offs between various pros and cons, underscoring the persisting necessity to expand the imaging toolkits. Here we present PACIFIC: photoactive immunofluorescence with iterative cleavage, a new modality of multiplex protein imaging methods. PACIFIC achieves iterative multiplexing by implementing photocleavable fluorophores for antibody labeling with one-step spin-column purification. PACIFIC requires no specialized instrument, no DNA encoding, or chemical treatments. We demonstrate that PACIFIC can resolve cellular heterogeneity in both formalin-fixed paraffin-embedded (FFPE) samples and fixed cells. To further highlight how PACIFIC assists discovery, we integrate PACIFIC with live-cell tracking and identify phosphor-p70S6K as a critical driver that governs U87 cell mobility. Considering the cost, flexibility, and compatibility, we foresee that PACIFIC can confer deep phenotyping capabilities to anyone with access to traditional immunofluorescence platforms.

多重蛋白质成像技术能够进行深入的表型分析,并提供有关生物样本的丰富空间信息。现有的方法取得了巨大的成功,但也在各种利弊之间进行了权衡,强调了扩展成像工具包的持续必要性。在这里,我们介绍了太平洋:迭代切割的光活性免疫荧光,一种新的多重蛋白质成像方法。PACIFIC通过一步旋转柱纯化实现抗体标记的可光裂解荧光团,实现迭代复用。PACIFIC不需要专门的仪器,不需要DNA编码或化学处理。我们证明PACIFIC可以解决福尔马林固定石蜡包埋(FFPE)样品和固定细胞中的细胞异质性。为了进一步强调PACIFIC如何帮助发现,我们将PACIFIC与活细胞跟踪相结合,并将磷酸-p70S6K确定为控制U87细胞迁移的关键驱动因素。考虑到成本、灵活性和兼容性,我们预计PACIFIC可以为任何使用传统免疫荧光平台的人提供深入的表型能力。
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引用次数: 0
Design and Synthesis of Copper Nanobiomaterials with Antimicrobial Properties 具有抗菌性能的纳米铜生物材料的设计与合成
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-04-11 DOI: 10.1021/acsbiomedchemau.2c00089
Clara Ortega-Nieto, Noelia Losada-Garcia, Benevides C. Pessela, Pilar Domingo-Calap and Jose M. Palomo*, 

In this work, nanostructured copper materials have been designed, synthetized, and evaluated in order to produce a more efficient and sustainable copper bionanohybrid with catalytical and antimicrobial properties. Thus, conditions are sought where the most critical steps are reduced or minimized, such as the use of reducing agents or the cryogenization step. In addition, the new materials have been characterized through different techniques, and their oxidative and reductive capacities, as well as their antimicrobial activity, have been evaluated. The addition of different quantities of a reducing agent in the synthesis method generated copper bionanohybrids with different metallic species, nanoparticles sizes, and structures. The antimicrobial properties of the bionanohybrids were studied against different strains of Gram-positive and Gram-negative bacteria through two different methods: by counting the CFU and via the disk diffusion test, respectively. The bionanohybrids have demonstrated that different efficiencies depending on the bacterial strain were confronted with. The Cu-PHOS-100% R hybrids with the highest percentage of reduction showed the best antimicrobial efficiency against Escherichia coli and Klebsiella pneumoniae bacteria (>96 or >77% in 4 h, respectively) compared to 31% bacteria reduction using Cu-PHOS-0% R. Also, the antimicrobial activity against Bacillus subtilis materials was obtained with Cu-PHOS-100% R (31 mm inhibition zone and 125 μg/mL minimum inhibitory concentration value). Interestingly, the better antimicrobial activity of the nanobiohybrids against Gram-positive bacteria Mycobacterium smegmatis was obtained with some with a lower reduction step in the synthesis, Cu-PHOS-10% R or Cu-PHOS-20% R (>94% bacterial reduction in 4 h).

在这项工作中,已经设计、合成和评估了纳米结构铜材料,以生产具有催化和抗菌性能的更高效和可持续的铜-生物纳米杂化物。因此,寻求减少或最小化最关键步骤的条件,例如使用还原剂或冷冻步骤。此外,通过不同的技术对新材料进行了表征,并对其氧化和还原能力以及抗菌活性进行了评估。在合成方法中添加不同量的还原剂产生了具有不同金属种类、纳米颗粒尺寸和结构的铜-生物纳米杂化物。采用菌落总数计数法和纸片扩散法两种不同的方法,研究了仿生杂交体对不同革兰氏阳性菌和革兰氏阴性菌的抗菌性能。仿生杂交体已经证明,不同菌株所面临的效率不同。与使用Cu-PHOS-0%R减少31%的细菌相比,具有最高减少百分比的Cu-PHOS-10%R杂交种对大肠杆菌和肺炎克雷伯菌显示出最佳的抗菌效率(在4小时内分别>96或>77%)。此外,Cu-PHOS-100%R(31mm抑菌带和125μ。有趣的是,纳米生物杂化物对革兰氏阳性菌耻垢分枝杆菌具有更好的抗菌活性,其中一些在合成中具有较低的还原步骤,Cu-PHOS-10%R或Cu-PHOS-20%R(4小时内细菌还原>94%)。
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引用次数: 1
Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity 噻唑类前药酯和衍生肽:合成和活性
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-04-11 DOI: 10.1021/acsbiomedchemau.2c00083
Andrew V. Stachulski*, Jean-Francois Rossignol, Sophie Pate, Joshua Taujanskas, Jonathan A. Iggo, Rudi Aerts, Etienne Pascal, Sara Piacentini, Simone La Frazia, M. Gabriella Santoro, Lieven van Vooren, Liesje Sintubin, Mark Cooper, Karl Swift and Paul M. O’Neill, 

Amino acid ester prodrugs of the thiazolides, introduced to improve the pharmacokinetic parameters of the parent drugs, proved to be stable as their salts but were unstable at pH > 5. Although some of the instability was due to simple hydrolysis, we have found that the main end products of the degradation were peptides formed by rearrangement. These peptides were stable solids: they maintained significant antiviral activity, and in general, they showed improved pharmacokinetics (better solubility and reduced clearance) compared to the parent thiazolides. We describe the preparation and evaluation of these peptides.

噻唑类的氨基酸酯前药,被引入以改善母体药物的药代动力学参数,被证明作为它们的盐是稳定的,但在pH>;5.尽管一些不稳定性是由于简单的水解,但我们发现降解的主要最终产物是通过重排形成的肽。这些肽是稳定的固体:它们保持了显著的抗病毒活性,总体而言,与母体噻唑类化合物相比,它们表现出更好的药代动力学(更好的溶解度和降低的清除率)。我们描述了这些肽的制备和评价。
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引用次数: 0
Zafirlukast Is a Promising Scaffold for Selectively Inhibiting TNFR1 Signaling Zafirlukast是选择性抑制TNFR1信号传导的有希望的支架
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-04-07 DOI: 10.1021/acsbiomedchemau.2c00048
Nagamani Vunnam, Mu Yang, Chih Hung Lo, Carolyn Paulson, William D. Fiers, Evan Huber, MaryJane Been, David M. Ferguson and Jonathan N. Sachs*, 

Tumor necrosis factor (TNF) plays an important role in the pathogenesis of inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. The biological effects of TNF are mediated by binding to TNF receptors, TNF receptor 1 (TNFR1), or TNF receptor 2 (TNFR2), and this coupling makes TNFR1-specific inhibition by small-molecule therapies essential to avoid deleterious side effects. Recently, we engineered a time-resolved fluorescence resonance energy transfer biosensor for high-throughput screening of small molecules that modulate TNFR1 conformational states and identified zafirlukast as a compound that inhibits receptor activation, albeit at low potency. Here, we synthesized 16 analogues of zafirlukast and tested their potency and specificity for TNFR1 signaling. Using cell-based functional assays, we identified three analogues with significantly improved efficacy and potency, each of which induces a conformational change in the receptor (as measured by fluorescence resonance energy transfer (FRET) in cells). The best analogue decreased NF-κB activation by 2.2-fold, IκBα efficiency by 3.3-fold, and relative potency by two orders of magnitude. Importantly, we showed that the analogues do not block TNF binding to TNFR1 and that binding to the receptor’s extracellular domain is strongly cooperative. Despite these improvements, the best candidate’s maximum inhibition of NF-κB is only 63%, leaving room for further improvements to the zafirlukast scaffold to achieve full inhibition and prove its potential as a therapeutic lead. Interestingly, while we find that the analogues also bind to TNFR2 in vitro, they do not inhibit TNFR2 function in cells or cause any conformational changes upon binding. Thus, these lead compounds should also be used as reagents to study conformational-dependent activation of TNF receptors.

肿瘤坏死因子(TNF)在类风湿性关节炎和克罗恩病等炎症性和自身免疫性疾病的发病机制中发挥着重要作用。TNF的生物学效应是通过与TNF受体、TNF受体1(TNFR1)或TNF受体2(TNFR2)结合介导的,这种偶联使得小分子疗法对TNFR1的特异性抑制对于避免有害副作用至关重要。最近,我们设计了一种时间分辨荧光共振能量转移生物传感器,用于高通量筛选调节TNFR1构象状态的小分子,并确定扎菲鲁司特是一种抑制受体激活的化合物,尽管效力较低。在这里,我们合成了16种扎菲鲁司特类似物,并测试了它们对TNFR1信号传导的效力和特异性。使用基于细胞的功能测定,我们鉴定了三种疗效和效力显著提高的类似物,每种类似物都诱导受体的构象变化(通过细胞中的荧光共振能量转移(FRET)测量)。最佳类似物将NF-κB活化降低了2.2倍,IκBα效率降低了3.3倍,相对效力降低了两个数量级。重要的是,我们发现类似物不会阻断TNF与TNFR1的结合,并且与受体的细胞外结构域的结合是强协同的。尽管有这些改进,但最佳候选物对NF-κB的最大抑制率仅为63%,为扎菲鲁司特支架的进一步改进留下了空间,以实现完全抑制并证明其作为治疗先导的潜力。有趣的是,虽然我们发现类似物在体外也与TNFR2结合,但它们不会抑制TNFR2在细胞中的功能,也不会在结合时引起任何构象变化。因此,这些先导化合物也应该用作研究TNF受体构象依赖性激活的试剂。
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引用次数: 0
X-ray Structure Characterization of the Selective Recognition of AT Base Pair Sequences 选择性识别AT碱基对序列的x射线结构表征
Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2023-04-05 DOI: 10.1021/acsbiomedchemau.3c00002
Edwin N. Ogbonna, Ananya Paul, Abdelbasset A. Farahat, J. Ross Terrell, Ekaterina Mineva, Victor Ogbonna, David W Boykin and W. David Wilson*, 

The rational design of small molecules that target specific DNA sequences is a promising strategy to modulate gene expression. This report focuses on a diamidinobenzimidazole compound, whose selective binding to the minor groove of AT DNA sequences holds broad significance in the molecular recognition of AT-rich human promoter sequences. The objective of this study is to provide a more detailed and systematized understanding, at an atomic level, of the molecular recognition mechanism of different AT-specific sequences by a rationally designed minor groove binder. The specialized method of X-ray crystallography was utilized to investigate how the sequence-dependent recognition properties in general, A-tract, and alternating AT sequences affect the binding of diamidinobenzimidazole in the DNA minor groove. While general and A-tract AT sequences give a narrower minor groove, the alternating AT sequences intrinsically have a wider minor groove which typically constricts upon binding. A strong and direct hydrogen bond between the N-H of the benzimidazole and an H-bond acceptor atom in the minor groove is essential for DNA recognition in all sequences described. In addition, the diamidine compound specifically utilizes an interfacial water molecule for its DNA binding. DNA complexes of AATT and AAAAAA recognition sites show that the diamidine compound can bind in two possible orientations with a preference for water-assisted hydrogen bonding at either cationic end. The complex structures of AAATTT, ATAT, ATATAT, and AAAA are bound in a singular orientation. Analysis of the helical parameters shows a minor groove expansion of about 1 Å across all the nonalternating DNA complexes. The results from this systematic approach will convey a greater understanding of the specific recognition of a diverse array of AT-rich sequences by small molecules and more insight into the design of small molecules with enhanced specificity to AT and mixed DNA sequences.

合理设计靶向特定DNA序列的小分子是调节基因表达的一种很有前途的策略。本报告的重点是一种二氨基苯并咪唑化合物,其与AT DNA序列的小凹槽的选择性结合在富含AT的人类启动子序列的分子识别中具有广泛的意义。本研究的目的是在原子水平上,通过合理设计的小凹槽粘合剂,对不同at特异性序列的分子识别机制提供更详细和系统的理解。利用X射线晶体学的专门方法研究了序列依赖性识别特性(一般而言,A区和交替的AT序列)如何影响二氨基苯并咪唑在DNA小凹槽中的结合。虽然一般和A区AT序列给出较窄的小凹槽,但交替的AT序列本质上具有较宽的小凹槽(其通常在结合时收缩)。苯并咪唑的N-H和小凹槽中的氢键受体原子之间的强而直接的氢键对于所描述的所有序列中的DNA识别是必不可少的。此外,二胺化合物特异性地利用界面水分子进行其DNA结合。AATT和AAAAAA识别位点的DNA复合物表明,二胺化合物可以在两个可能的方向上结合,在任一阳离子末端都优选水辅助氢键。AAATTT、ATAT、ATATAT和AAAA的复杂结构以奇异方向结合。对螺旋参数的分析显示,在所有非交替DNA复合物中,凹槽的轻微扩展约为1Å。这种系统方法的结果将传达对小分子对富含AT的各种序列的特异性识别的更深入理解,以及对对AT和混合DNA序列具有增强特异性的小分子的设计的更多见解。
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引用次数: 1
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ACS Bio & Med Chem Au
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