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Development of coumarin-inspired bifunctional hybrids as a new class of anti-Alzheimer's agents with potent in vivo efficacy. 香豆素激发的双功能杂交体的开发作为一类新的抗阿尔茨海默病药物具有强大的体内疗效。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-11 DOI: 10.1039/d4md00782d
Atamjit Singh, Aman Sharma, Karanvir Singh, Kirandeep Kaur, Pallvi Mohana, Jignesh Prajapati, Uttam Kaur, Dweipayan Goswami, Saroj Arora, Renu Chadha, Preet Mohinder Singh Bedi

Considering the multifactorial and complex nature of Alzheimer's disease and the requirement of an optimum multifunctional anti-Alzheimer's agent, a series of triazole tethered coumarin-eugenol hybrid molecules was designed as potential multifunctional anti-Alzheimer's agents using donepezil and a template. The designed hybrid molecules were synthesized via a click chemistry approach and preliminarily screened for cholinesterase and Aβ1-42 aggregation inhibition. Among them, AS15 emerged as a selective inhibitor of AChE (IC50 = 0.047 μM) over butyrylcholinesterase (BuChE: IC50 ≥ 10 μM) with desired Aβ1-42 aggregation inhibition (72.21% at 50 μM) properties. In addition, AS15 showed protective effects against DNA damage caused by hydroxyl radicals originating from H2O2. Molecular docking and simulation studies confirmed the favorable interactions of AChE and the Aβ1-42 monomer desired for their inhibition. AS15 exhibited an LD50 value of 300 mg kg-1 and showed significant improvements in memory and learning behavior in scopolamine-induced cognition impairment mouse-based animal models (Y-maze test and Morris water maze test) for behavioral analysis. Overall outcomes suggest AS15 as a potential preclinical multifunctional candidate for the management of Alzheimer's disease, and it serves as a promising lead for further development of potent and safer multifunctional anti-Alzheimer's agents.

考虑到阿尔茨海默病的多因素和复杂性,以及对最佳多功能抗阿尔茨海默病药物的需求,以多奈哌齐为模板,设计了一系列三唑系香豆素-丁香酚杂化分子作为潜在的多功能抗阿尔茨海默病药物。设计的杂化分子通过点击化学方法合成,并初步筛选了胆碱酯酶和a - β1-42聚集抑制作用。其中,AS15作为乙酰胆碱酯酶(BuChE: IC50≥10 μM)的选择性抑制剂(IC50 = 0.047 μM),具有良好的a - β1-42聚集抑制性能(50 μM时为72.21%)。此外,AS15对H2O2产生的羟基自由基引起的DNA损伤具有保护作用。分子对接和模拟研究证实了乙酰胆碱酯酶与a - β1-42单体的良好相互作用。AS15的LD50值为300 mg kg-1,在东莨菪碱诱导的认知障碍小鼠动物模型(y迷宫实验和Morris水迷宫实验)中表现出显著的记忆和学习行为改善。总体结果表明,AS15是治疗阿尔茨海默病的潜在临床前多功能候选药物,它是进一步开发更有效、更安全的多功能抗阿尔茨海默病药物的有希望的先导。
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引用次数: 0
An estrogen receptor β-targeted near-infrared probe for theranostic imaging of prostate cancer.
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-11 DOI: 10.1039/d4md00767k
Junhong Dai, Yihe Wu, Xiaofei Deng, Hai-Bing Zhou, Chune Dong

Estrogen receptor β (ERβ) is aberrantly expressed in castration-resistant prostate cancer (CRPC). Therefore, a diagnostic and therapeutic ERβ probe not only helps to reveal the complex role of ERβ in prostate cancer (PCa), but also promotes ERβ-targeted PCa therapy. Herein, we reported a novel ERβ-targeted near-infrared fluorescent probe D3 with both imaging and therapeutic functions, which had the advantages of high ERβ selectivity, good optical performance, and strong anti-interference ability. In addition, it displayed excellent antiproliferative activity in CRPC cells. Finally, D3 was also successfully applied to the in vivo imaging of ERβ in the prostate cancer mouse model. Thus, this ERβ-targeted near-infrared fluorescent probe can be used as a potential tool for the study of ERβ-targeted diagnostic and therapeutic PCa.

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引用次数: 0
Sulphonyl thiourea compounds containing pyrimidine as dual inhibitors of I, II, IX, and XII carbonic anhydrases and cancer cell lines: synthesis, characterization and in silico studies. 含嘧啶的磺基硫脲化合物作为I、II、IX和XII碳酸酐酶和癌细胞系的双重抑制剂:合成、表征和硅研究。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-11 DOI: 10.1039/d4md00816b
Nguyen Dinh Thanh, Vu Ngoc Toan, Vu Minh Trang

Some novel sulphonyl thiourea derivatives (7a-m) containing 4,6-diarylpyrimidine rings were designed and synthesized using a one-pot procedure. These compounds exhibited remarkable dual inhibitory activity against human carbonic anhydrase hCA I, hCA II, hCA IX, and XII isoenzymes and some cancer cell lines. Among them, some thioureas had significantly more potent inhibitory activities in the order of 7l > 7c > 7f (against the hCA I isoform), 7f > 7b > 7c (against the hCA II isoform), 7c > 7g > 7a > 7b (against the hCA IX isoform), and 7d > 7c > 7g > 7f (against the hCA XII isoform). The obtained inhibitory activity data against the hCA IX and XII isoforms showed that compound 7c was the most potent inhibitor in this sulphonyl thiourea series against enzyme hCA IX, with K I = 125.1 ± 12.4 nM, while compound 7d was the most potent inhibitor against enzyme hCA XII, with K I = 111.0 ± 12.3 nM. Compound 7c exhibited strong inhibitory activity among all four tested hCA enzymes, while thiourea 7f was a potent inhibitor for enzymes hCA I, II and XII. All these compounds demonstrated non-competitive inhibition of both enzymes. Some selected potential inhibitory compounds, including 7c, 7d, and 7g, exhibited remarkable cytotoxic activity against human cancer cell lines, including human breast adenocarcinoma (MCF-7), human liver adenocarcinoma (HepG2), human cervical epithelial carcinoma (HeLa), and human lung adenocarcinoma cells (A549). These compounds exhibited low cytotoxicity in the WI-38 cell line. The compounds 7c and 7d were the most potent inhibitors against tumour-associated hCA IX and hCA XII isoenzymes. Furthermore, these compounds exhibited remarkable inhibition against some cancer cell lines, such as MCF-7, HepG2, HeLa, and A549. They were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7c and 7d were the most promising derivatives in this series owing to their significant effects on the studied hCA IX and hCA XII isoenzymes, respectively. The results showed that the sulphonyl thiourea moiety was deeply accommodated in the active site and interacted with zinc ions in the receptors.

设计并合成了一些新型的含有4,6-二芳基嘧啶环的磺胺基硫脲衍生物(7a-m)。这些化合物对人碳酸酐酶hCA I、hCA II、hCA IX和hCA XII同工酶和一些癌细胞具有显著的双重抑制活性。其中,部分硫脲对hCA I异构体的抑制活性为71> 7c >7f,对hCA II异构体的抑制活性为71> 7b >c,对hCA IX异构体的抑制活性为71> 7g > 7a > 7b,对hCA XII异构体的抑制活性为71> 7c > 7g > 7f。对hCA IX和hCA XII亚型的抑制活性数据表明,化合物7c对hCA IX酶的抑制作用最强,K I = 125.1±12.4 nM,而化合物7d对hCA XII酶的抑制作用最强,K I = 111.0±12.3 nM。化合物7c对四种hCA酶均有较强的抑制活性,而硫脲7f对hCA I、II和XII酶均有较强的抑制作用。所有这些化合物均表现出对两种酶的非竞争性抑制作用。一些选定的潜在抑制化合物,包括7c, 7d和7g,对人类癌细胞系,包括人乳腺腺癌(MCF-7),人肝腺癌(HepG2),人宫颈上皮癌(HeLa)和人肺腺癌细胞(A549)显示出显著的细胞毒活性。这些化合物在WI-38细胞系中表现出较低的细胞毒性。化合物7c和7d是肿瘤相关hCA IX和hCA XII同工酶的最有效抑制剂。此外,这些化合物对MCF-7、HepG2、HeLa和A549等癌细胞具有显著的抑制作用。他们进行了分子对接和分子动力学模拟的硅筛选。体外和硅内实验结果表明,化合物7c和7d分别对hCA IX和hCA XII同工酶具有显著的影响,是该系列中最有前途的衍生物。结果表明,巯基硫脲部分被深度安置在活性位点,并与受体中的锌离子相互作用。
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引用次数: 0
Probing non-peptide agonists binding at the human nociceptin/orphanin FQ receptor: a molecular modelling study. 探测非肽激动剂与人类痛觉肽/孤啡肽FQ受体的结合:分子模型研究。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-10 DOI: 10.1039/d4md00747f
Matteo Gozzi, Davide Malfacini, Valentina Albanese, Salvatore Pacifico, Delia Preti, Remo Guerrini, Girolamo Calò, Antonella Ciancetta

The N/OFQ-NOP receptor is a fascinating peptidergic system with the potential to be exploited for the development of analgesic drugs devoid of side effects associated with classical opioid signalling modulation. To date, up to four X-ray and cryo-EM structures of the NOP receptor in complex with the endogenous peptide agonist N/OFQ and three small molecule antagonists have been solved and released. Despite the available structural information, the details of selective small molecule agonist binding to the NOP receptor in the active state remain elusive. In this study, by leveraging the available structural information and using N/OFQ(1-13)-NH2 as a reference compound, we developed a computational protocol based on docking followed by short molecular dynamics (MD) simulations that can suggest small molecule agonist binding modes at the NOP receptor that are reproducible and stable over time in the solvated membrane-embedded receptor active state and in agreement with known structure-activity relationship (SAR) data.

N/OFQ-NOP受体是一个令人着迷的肽能系统,有潜力用于开发无副作用的镇痛药物,与经典的阿片信号调节相关。迄今为止,NOP受体与内源性肽激动剂N/OFQ和三种小分子拮抗剂复合物的x射线和低温电镜结构已被破解和释放。尽管有可用的结构信息,但选择性小分子激动剂在活性状态下与NOP受体结合的细节仍然难以捉摸。在这项研究中,利用现有的结构信息,并以N/OFQ(1-13)-NH2作为参考化合物,我们开发了一种基于对接和短分子动力学(MD)模拟的计算方案,该方案可以建议小分子激动剂在NOP受体上的结合模式,该模式在溶剂化膜嵌入受体活性状态下可重复且稳定,并且与已知的结构-活性关系(SAR)数据一致。
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引用次数: 0
Exploiting the DCAF16–SPIN4 interaction to identify DCAF16 ligands for PROTAC development† 利用DCAF16- spin4相互作用鉴定用于PROTAC开发的DCAF16配体。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-06 DOI: 10.1039/D4MD00681J
Isabella A. Riha, Miguel A. Campos, Xiaokang Jin, Fiona Y. Wang, Chenlu Zhang, Sara F. Dunne, Benjamin F. Cravatt and Xiaoyu Zhang

Traditional small molecule drugs often target protein activity directly, but challenges arise when proteins lack suitable functional sites. An alternative approach is targeted protein degradation (TPD), which directs proteins to cellular machinery for proteolytic degradation. Recent studies have identified additional E3 ligases suitable for TPD, expanding the potential of this approach. Among these, DCAF16 has shown promise in facilitating protein degradation through both PROTAC and molecular glue mechanisms. In this study, we developed a homogeneous time resolved fluorescence (HTRF) assay to discover new DCAF16 binders. Using an in-house electrophile library, we identified two diastereomeric compounds, with one engaging DCAF16 at cysteines C177–179 and another reducing its expression. We demonstrated that the compound covalently engaging DCAF16 can be transformed into a PROTAC capable of degrading FKBP12.

传统的小分子药物通常直接针对蛋白质的活性,但当蛋白质缺乏合适的功能位点时,就会出现挑战。另一种方法是靶向蛋白质降解(TPD),它将蛋白质引导到细胞机制中进行蛋白水解降解。最近的研究发现了更多适合 TPD 的 E3 连接酶,扩大了这种方法的潜力。其中,DCAF16 已显示出通过 PROTAC 和分子胶机制促进蛋白质降解的前景。在这项研究中,我们开发了一种均相时间分辨荧光(HTRF)测定法来发现新的 DCAF16 结合体。利用内部亲电子库,我们发现了两种非对映化合物,其中一种能与半胱氨酸 C177-179 上的 DCAF16 结合,另一种则能降低其表达。我们证明,共价结合 DCAF16 的化合物可以转化为能够降解 FKBP12 的 PROTAC。
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引用次数: 0
Thiazole-fused androstenone and ethisterone derivatives: potent β- and γ-actin cytoskeleton inhibitors to treat melanoma tumors. 噻唑融合雄甾酮和乙甾酮衍生物:治疗黑色素瘤的强效β-和γ-肌动蛋白细胞骨架抑制剂。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-06 DOI: 10.1039/d4md00719k
Sanjay Adhikary, Subrata Roy, Shailesh Budhathoki, Siam Chowdhury, Abbey Stillwell, Alexei G Basnakian, Alan Tackett, Nathan Avaritt, Mohamed Milad, Mohammad Abrar Alam

Melanoma, the most fatal form of skin cancer, often becomes resistant to the current therapeutic approaches in most patients. To explore new treatment options, fused thiazole derivatives were synthesized, and several of these compounds demonstrated potent anti-melanoma activity both in vitro and in vivo. These compounds exhibited significant cytotoxicity against melanoma cell lines at low concentrations. The lead molecules induced apoptosis and caused G2/M phase cell cycle arrest to a lesser extent. These compounds also displayed remarkable antimetastatic activities in several cell-based and molecular assays, significantly inhibiting key processes of metastasis, such as cell migration and adhesion. mRNA sequencing revealed significant downregulation of β-actin (ACTB) and γ-actin (ACTG1) at the transcriptional level, and a similar effect was observed at the protein level by western immunoblotting and proteomics assays. Actin-rich membrane protrusions formation is crucial for facilitating metastasis by promoting cell migration. Fluorescence microscopy demonstrated that compounds E28 and E47 inhibited the formation of these membrane protrusions and impaired actin cytoskeleton dynamics. Docking studies suggested the lead compounds may suppress tumor proliferation and metastasis by targeting the mechanistic target of Rapamycin complex 2 (mTORC2). All these findings unanimously indicated the translational perspective of ethisterone and androstenone fused thiazole derivatives as potent antimetastatic and antimelanoma agents. In a preclinical mouse melanoma model, compounds E2 and E47 significantly reduced tumor growth and greatly improved overall mice survival, while showing a favorable safety profile based on a comprehensive blood plasma metabolite profile. These lead molecules also displayed promising physicochemical properties, making them strong candidates for further drug development studies.

黑色素瘤是最致命的一种皮肤癌,对大多数患者来说,目前的治疗方法往往会产生抗药性。为了探索新的治疗选择,合成了融合噻唑衍生物,其中一些化合物在体外和体内都显示出有效的抗黑色素瘤活性。这些化合物在低浓度下对黑色素瘤细胞系表现出显著的细胞毒性。铅分子诱导细胞凋亡,并在较小程度上引起G2/M期细胞周期阻滞。这些化合物在一些基于细胞和分子的实验中也显示出显著的抗转移活性,显著抑制转移的关键过程,如细胞迁移和粘附。mRNA测序结果显示β-肌动蛋白(ACTB)和γ-肌动蛋白(ACTG1)在转录水平上显著下调,western免疫印迹和蛋白质组学分析在蛋白水平上也观察到类似的作用。富肌动蛋白膜突起的形成是通过促进细胞迁移促进转移的关键。荧光显微镜显示,化合物E28和E47抑制了这些膜突起的形成,并破坏了肌动蛋白细胞骨架动力学。对接研究表明,先导化合物可能通过靶向雷帕霉素复合物2 (Rapamycin complex 2, mTORC2)的机制靶点抑制肿瘤增殖和转移。所有这些结果一致表明乙甾酮和雄烯酮融合噻唑衍生物作为有效的抗转移和抗黑色素瘤药物的翻译前景。在临床前小鼠黑色素瘤模型中,化合物E2和E47显著降低了肿瘤生长,大大提高了小鼠的总体存活率,同时基于综合血浆代谢物谱显示出良好的安全性。这些铅分子也显示出有希望的物理化学性质,使它们成为进一步药物开发研究的有力候选者。
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引用次数: 0
Design and synthesis of novel cathepsin C inhibitors with anti-inflammatory activity† 新型抗炎组织蛋白酶C抑制剂的设计与合成。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-03 DOI: 10.1039/D4MD00730A
Xiaobao Shen, Nan Li, Miao Liu, Xuanzheng Han, Yazhi Wang, Jingwen Jia, Fufang Wu, Hongwei Chen and Xinhua Liu

Cathepsin C (Cat C) is a potential candidate for addressing inflammatory conditions associated with neutrophil serine proteases (NSPs). The high reactivity of electrophilic warheads and the metabolic instability of peptide structures are among the primary challenges in developing potent cathepsin C inhibitors. Compound 36, a lead compound derived from compound 1 through structure-based drug design and structure–activity relationship (SAR), exhibited strong Cat C inhibitory activity with an IC50 value of 437 nM. It also showed a substantial enhancement in overall anti-inflammatory activity, achieving an inhibitory effect on NO release at 4.1 μM. Furthermore, molecular docking was conducted to analyze the mode of action with Cat C. And cell thermal shift analysis (CETSA) revealed that this compound increases the temperature tolerance of Cat C in a concentration-dependent manner, suggesting strong binding to the target Cat C. Prolonged pharmacological inhibition activity may result in the depletion of active NSPs.

组织蛋白酶C (Cat C)是解决与中性粒细胞丝氨酸蛋白酶(NSPs)相关的炎症状况的潜在候选者。亲电弹头的高反应性和肽结构的代谢不稳定性是开发有效的组织蛋白酶C抑制剂的主要挑战。化合物36是通过结构药物设计和构效关系(SAR)从化合物1衍生出的先导化合物,具有较强的Cat C抑制活性,IC50值为437 nM。整体抗炎活性也有显著增强,在4.1 μM时对NO释放有抑制作用。通过分子对接分析其与Cat C的作用模式。细胞热移分析(CETSA)显示,该化合物以浓度依赖的方式增加Cat C的耐温性,表明其与靶Cat C的结合较强,药理抑制活性延长可能导致活性nsp的消耗。
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引用次数: 0
Correction: A comprehensive apoptotic assessment of niloticin in cervical cancer cells: a tirucallane-type triterpenoid from Aphanamixis polystachya (Wall.) Parker 更正:宫颈癌细胞中niloticin的全面凋亡评估:一种来自Aphanamixis polystachya (Wall.)的三萜三烯烷型。帕克。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-02 DOI: 10.1039/D4MD90049A
Anuja Gracy Joseph, Mohanan Biji, Vishnu Priya Murali, Daisy R. Sherin, Alisha Valsan, Vimalkumar P. Sukumaran, Kokkuvayil Vasu Radhakrishnan and Kaustabh Kumar Maiti

Correction for ‘A comprehensive apoptotic assessment of niloticin in cervical cancer cells: a tirucallane-type triterpenoid from Aphanamixis polystachya (Wall.) Parker’ by Anuja Gracy Joseph et al., RSC Med. Chem., 2024, 15, 3444–3459, https://doi.org/10.1039/D4MD00318G.

[更正文章DOI: 10.1039/D4MD00318G.]。
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引用次数: 0
Hepatocyte targeting via the asialoglycoprotein receptor 通过asialal糖蛋白受体靶向肝细胞。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-02 DOI: 10.1039/D4MD00652F
Fabricio Ramírez-Cortés and Petra Ménová

This review highlights the potential of asialoglycoprotein receptor (ASGPR)-mediated targeting in advancing liver-specific treatments and underscores the ongoing progress in the field. First, we provide a comprehensive examination of the nature of ASGPR ligands, both natural and synthetic. Next, we explore various drug delivery strategies leveraging ASGPR, with a particular emphasis on the delivery of therapeutic nucleic acids such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). An in-depth analysis of the current status of RNA interference (RNAi) and ASO-based therapeutics is included, detailing approved therapies and those in various stages of clinical development (phases 1 to 3). Afterwards, we give an overview of other ASGPR-targeted conjugates, such as those with peptide nucleic acids or aptamers. Finally, targeted protein degradation of extracellular proteins through ASGPR is briefly discussed.

这篇综述强调了asialalglycoprotein receptor (ASGPR)介导的靶向治疗在推进肝脏特异性治疗中的潜力,并强调了该领域正在进行的进展。首先,我们对ASGPR配体的性质进行了全面的检查,包括天然的和合成的。接下来,我们探索利用ASGPR的各种药物递送策略,特别强调治疗性核酸的递送,如小干扰rna (sirna)和反义寡核苷酸(ASOs)。深入分析了RNA干扰(RNAi)和基于aspr的治疗方法的现状,详细介绍了已批准的治疗方法和处于临床开发不同阶段(1至3期)的治疗方法。随后,我们概述了其他asgpr靶向偶联物,例如具有肽核酸或适体的偶联物。最后简要讨论了ASGPR对细胞外蛋白的靶向降解。
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引用次数: 0
Design, synthesis and antiviral evaluation of triazole-linked 7-hydroxycoumarin-monoterpene conjugates as inhibitors of RSV replication. 三唑- 7-羟基香豆素-单萜偶联物RSV复制抑制剂的设计、合成和抗病毒评价。
IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-12-02 DOI: 10.1039/d4md00728j
Dmitry O Tsypyshev, Artem M Klabukov, Daria N Razgulaeva, Anastasia V Galochkina, Anna A Shtro, Sophia S Borisevich, Tatyana M Khomenko, Konstantin P Volcho, Nina I Komarova, Nariman F Salakhutdinov

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in babies across the world. Irrespective of progress in the development of RSV vaccines, effective small molecule drugs are still not available on the market. Based on our previous data we designed and synthesized triazole-linked coumarin-monoterpene hybrids and showed that they are indeed effective in inhibiting the RSV replication. The most effective compounds are active against both RSV serotypes, A and B, with IC50 in the low micromolar or submicromolar range of concentrations. These are the most active coumarin derivatives found so far. Compound 45 combining 3,7-dimethyloctane and cyclopentane-annealed coumarin fragments has a selectivity index of 160 for serotype A and 1147 for serotype B. According to the results of the time-of-addition experiments, the conjugates are active at the early stages of the virus cycle. Based on biological evaluation and molecular modeling data, RSV F protein is a possible target.

呼吸道合胞病毒(RSV)是导致全球婴儿急性下呼吸道感染的主要原因。尽管 RSV 疫苗的研发取得了进展,但市场上仍然没有有效的小分子药物。根据以往的数据,我们设计并合成了三唑联香豆素-单萜杂交化合物,结果表明它们确实能有效抑制 RSV 的复制。最有效的化合物对两种 RSV 血清型(A 型和 B 型)都有活性,其 IC50 在低微摩尔或亚微摩浓度范围内。这些是迄今为止发现的最有效的香豆素衍生物。结合了 3,7 二甲基辛烷和环戊烷退火香豆素片段的化合物 45 对血清型 A 的选择性指数为 160,对血清型 B 的选择性指数为 1147。根据生物学评估和分子模型数据,RSV F 蛋白是一个可能的靶标。
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引用次数: 0
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