靶向整合过程不同步骤的HIV-1整合酶抑制剂的结构类型和研究进展

HIV-1整合酶是病毒复制所必需的三个基本酶之一, 为病毒所特有, 人体无对应的酶, 因此整合酶是理想的抗HIV药物设计的新靶标. HIV-1整合酶催化病毒DNA插入宿主染色体的过程涉及到整合酶与前病毒DNA形成整合前复合物、病毒DNA的3’末端切断和DNA链转移等步骤, 目前研究得最多的HIV-1整合酶抑制剂是抑制链转移反应的芳基二酮酸化合物, 其中的电子等排体衍生物Raltegravir (MK-0518)于2007年10月被美国食品药品管理局(FDA)批准上市, 而GS-9137处于三期临床试验, 此外还有多个处于临床前研究和临床阶段的药物. 根据抑制剂的不同作用机理, 本综述介绍了近年来所报道的HIV-1整合酶抑制剂的结构类型、药效团模型、研究进展及化学合成, 将整合酶抑制剂分为链转移反应抑制剂、整合酶-DNA结合抑制剂、整合酶3’端切除反应抑制剂、非专一性整合酶抑制剂以及多肽类抑制剂等几大类. 其中链转移反应抑制剂结构类型最丰富、发展最快. 整合酶抑制剂的出现丰富了高效抗逆转录病毒疗法(HAART), 为多重抗药性艾滋病患者提供了新的有效的治疗方案.     

结构多样的HIV-1整合酶抑制剂:过去、现在和未来

HIV-1整合酶是逆转录病毒复制的必需酶,它催化病毒DNA与宿主染色体DNA的整合,而且在人类细胞中没有类似物,因此成为治疗艾滋病的富有吸引力和合理的靶标.最近十年,一大批HIV-1整合酶抑制剂被鉴定出来,其中一些化合物显示选择性的抑制HIV-1整合酶和阻断病毒复制的活性,而最有影响的两类抑制剂是含邻苯二酚的多羟基芳环化合物和最近报道的芳基β-二酮酸类化合物.全面综述了用于HIV-1整合酶抑制剂研究以发展抗HIV新药的不同种类的化合物,包括苯并咪唑类衍生物、核苷类、多肽、羟基取代的芳环化合物及二酮酸类化合物等,并阐述了这些化合物中对抑制活性重要的结构特征.同时也介绍了HIV-1整合酶的结构、功能以及HIV-1整合酶抑制剂的设计原理和作用机制.     

HIV-1整合酶与抑制剂LCA的结合模式及抗药性研究

Ⅰ型人体免疫缺陷病毒(HIV-1)整合酶(integrase, IN)是病毒生命周期中一个重要的酶, 也是研究抗HIV新药的一个重要靶点. 运用多构象分子对接和分子动力学(molecular dynamics, MD)模拟, 研究了野生型整合酶核心区及G140S点突变的突变态整合酶核心区与抑制剂L-菊苣酸(L-chicoric acid, LCA)的结合模式, 并基于该结合模式探讨了G140S突变态整合酶对抑制剂LCA的抗药性. 结果表明: LCA结合到G140S突变态整合酶核心区中的位置与结合到野生型整合酶核心区的位置不同, 结合位置的差异导致LCA抑制作用的部分丧失; IN功能Loop区的柔性以及Mg²⁺离子与三个关键残基D64, D116和E152之间的相互作用有助于IN发挥生物学功能; G140S突变态整合酶核心区中的E152与LCA的排斥作用、K159与LCA结合能力的变弱以及Y143指向IN的口袋区是产生抗药性的重要原因. 这些模拟结果与实验结果吻合, 可为基于IN的抗HIV药物分子设计提供一些有用信息.     

基于靶标结构及作用机制的抗艾滋病药物研究进展

人体免疫缺陷病毒(Human immunodeficiency virus,HIV)是一种主要以CD4~+T淋巴细胞和巨噬细胞等免疫细胞为靶点的感染性逆转录病毒,HIV感染的最终阶段为出现获得性免疫缺陷综合征(Acquired immunodeficiency syndrome,AIDS).HIV迄今为止已经夺去近3300万人生命,是全球最大的公共卫生挑战之一.自从抗逆转录病毒治疗(Antiretrovial therapy,ART)出现以后,抗逆转录药物的联合使用使艾滋病从致死性疾病变成慢性可控性疾病.为了开发新的抗艾滋病药物,基于病毒复制周期中的不同靶标将近年发展的抗艾滋病药物进行分类简述,重点关注于药物的作用机制研究、临床应用现状及未来发展方向.     

新型非拟肽磺胺类HIV蛋白酶抑制剂Darunavir的研究进展

综述新型非拟肽磺胺类人类免疫缺陷病毒(HIV)蛋白酶抑制剂Darunavir (TMC-114)的发现, 抗病毒的活性, 分子模拟以及结构优化的研究进展. Darunavir不但对野生型的HIV蛋白酶有很好的抑制活性, 而且对多种抗性突变的HIV蛋白酶也有良好的活性, 是针对耐药性HIV所开发的新药.     

新型N-3位酰胺连噻唑烷-4-酮二芳基衍生物的设计合成及HIV逆转酶抑制活性

以氨基酸酯为原料,在微波辐射条件下合成了系列N-3位含酯基的噻唑烷-4-酮衍生物,经水解并酰胺缩合制备了N-3位酰胺键连接嘧啶胺的二芳基噻唑烷-4-酮衍生物.化合物通过人类免疫缺陷病毒(HIV)逆转酶(RT)试剂盒(比色法)评价了其酶抑制活性.活性结果表明,部分化合物如5bb,5bc,5cb和5cc能有效地抑制HIV逆转酶的活性,IC_(50)值分别为4.15,3.53,4.61和4.06μmol/L.构效关系表明N-3位2个碳的柔性侧链以及亲脂基如甲基的引入将有利于化合物的抗HIV逆转录酶活性.     

香豆素类衍生物的合成

由人免疫缺陷病毒 ( HIV)感染引起的免疫缺陷综合症 ( AIDS)——艾滋病 ,是人类致命疾病之一。世界各国都在致力于寻找抗艾滋病药物 ,其中一个研究热点是通过大规模筛选寻找生物活性较强的小分子非肽类抑制剂 ,然后进行结构优化 ,以期找到新一代的抗艾滋病药物。香豆素类衍生物是一类具有抗病毒等许多生物活性的化合物 ,一直被人们所重视。 1 992年 ,从马来西亚热带雨林植物 Calophllum L anigerum中分离出具有抗艾滋病病毒活性的香豆素类化合物 Calanolides[1] 。同时 ,由于香豆素类化合物合成相对简单 ,生物利用度高 ,促使人们在这个…     

核苷5'-硫代磷酰氨基酸酯电喷雾质谱研究

核苷磷酰氨基酸酯化合物是1类倍受重视的药物,特别是它可作为寡聚核苷酸的类似物用于反义药物[1].核苷逆转录酶抑制剂被批准用于治疗爱滋病(AIDS),目前普遍使用的抗HIV核苷类似物中,2',3'-双脱氧核苷(ddNs)具有良好的疗效[2],它的抗病毒的可能机理是在细胞激酶的作用下,5'-羟基发生相继的磷酸化生成三磷酸核苷,然后通过HIV-逆转录酶进入病毒DNA的合成,由于ddNs 3'-位没有相应的羟基存在,使得病毒DNA的合成得以终止.     

微量元素与艾滋病相关标志物

人类免疫缺陷病毒（HIV）感染病程监督是防治艾滋病的重要措施和手段。阐述了微量元素在HIV病变进程中的变化及与其它相关标志物的关系,内容包括：微量元素与HIV病变、微量元素与CD4淋巴细胞、微量元素与谷胱甘肽、微量元素与HIV消瘦综合征,以及微量元素与炎性反应标志等5个方面。迄今的研究表明,微量元素可以作为反映HIV感染疾病进展的一种新的替代标志物。     

Synthesis and HIV-1 integrase inhibition activity of some N-arylindoles

Eight simple N-arylindoles were designed, synthesized and evaluated as human immunodeficiency virus (HIV)-1 integrase inhibitors in vitro for the first time. Among these compounds, 3b, 3e and 3g demonstrated significant anti-HIV-1 integrase activity. Especially 3b showed the highest anti-HIV-1 integrase activity with EC50 value of 7.88 microg/ml and TI value of 24.61. Meantime, some structure-activity relationships were also observed and will provide a new lead for design and discovery of more potent N-arylindoles as HIV-1 integrase inhibitors.     

A concise synthesis of HIV integrase inhibitors bearing the dipyridone acid motif

An efficient route to dipyridone acid HIV integrase inhibitors is developed. The key steps include a one-pot three-step formation of the core template (containing one point of structural diversity) followed by a regioselective benzylation and in situ deprotection to afford the title compounds.     

苯乙烯基喹啉磺酰胺衍生物的设计、合成与 HIV整合酶抑制活性的研究

在运用比较分子场分析方法(CoMFA)分析了38个苯乙烯基喹啉类衍生物的三维定量构效关系的基础上, 根据立体, 静电以及氢键特征, 设计合成了一系列苯乙烯基喹啉磺酰胺衍生物并考察了它们的HIV整合酶抑制活性, 同时分析了所合成化合物的波谱特点.     

Pharmacophore modelling and electronic feature analysis of hydroxamic acid derivatives,the HIV integrase inhibitors

Hydroxamic acid derivatives with metal ion binding properties were collected from the literature to generate a pharmacophore and 3D-QSAR model for HIV strand transfer inhibition. The derived pharmacophore model (AAAHRR) recognizes both metal ion binding site and hydrophobic group. The QSAR model generated using this hypothesis expressed statistical significance (r ² = 0.971 for the training set and q ² = 0.913 for the test set). The ability of this pharmacophore model to retrieve other metal ion binding inhibitors was examined by screening the ChemBank database (ligandinfo) incorporated with 10 known strand transfer inhibitors. The studied favourable and unfavourable contours of chemical features (H-bond donor, acceptor and hydrophobic sites) revealed the role of hydrophobic substitution at the fluorobenzene ring and cyclization of the metal ion binding hydroxamic acid in effective integrase inhibition. Analysis of the frontier orbitals, HOMO and LUMO revealed that the nucleophilic / electrophilic interactions depend on the significant overlapping observed at the azaindole and hydroxamic acid groups. In essence, the generated pharmacophore model is competent enough to disclose the essential site-specific interactions involved in the inhibition of HIV integrase, and hence can be used in virtual screening to identify novel scaffolds as leads with increased anti-viral potency.     

用分子模拟方法研究HIV-1整合酶与咖啡酰基类抑制剂的相互作用

用分子对接和分子动力学(MD)模拟方法研究了一类咖啡酰基和没食子酰基类HIV-1整合酶抑制剂与整合酶之间的相互作用模式, 结果表明该类抑制剂分子上的两个侧链基团(咖啡酰基或没食子酰基)与整合酶的DDE基序之间的相互作用对抑制整合酶活性起到关键作用. 当侧链基团为没食子酰基时, 可以提高该类抑制剂与整合酶的结合能力. 采用线性相互作用能方法(LIE)计算了该类抑制剂与整合酶之间的结合自由能, 预测值与实验值相吻合, 均方根偏差RMSD为1.39 kJ•mol^-1, 以上结果可为基于结构的HIV-1整合酶抑制剂设计提供有用的信息.     

Targeting the Integrated Stress Response Kinase GCN2 to Modulate Retroviral Integration

Multiple viral targets are now available in the clinic to fight HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients due to resistance, with or without treatment-adherence glitches. Accordingly, it is important to better understand how HIV and other retroviruses replicate in order to propose alternative antiviral strategies. Recent studies have shown that multiple cellular factors are implicated during the integration step and, more specifically, that integrase can be regulated through post-translational modifications. We have shown that integrase is phosphorylated by GCN2, a cellular protein kinase of the integrated stress response, leading to a restriction of HIV replication. In addition, we found that this mechanism is conserved among other retroviruses. Accordingly, we developed an in vitro interaction assay, based on the AlphaLISA technology, to monitor the integrase-GCN2 interaction. From an initial library of 133 FDA-approved molecules, we identified nine compounds that either inhibited or stimulated the interaction between GCN2 and HIV integrase. In vitro characterization of these nine hits validated this pilot screen and demonstrated that the GCN2-integrase interaction could be a viable solution for targeting integrase out of its active site.     

Virtual screening of the SAMPL4 blinded HIV integrase inhibitors dataset

Several combinations of docking software and scoring functions were evaluated for their ability to predict the binding of a dataset of potential HIV integrase inhibitors. We found that different docking software were appropriate for each one of the three binding sites considered (LEDGF, Y3 and fragment sites), and the most suitable two docking protocols, involving Glide SP and Gold ChemScore, were selected using a training set of compounds identified from the structural data available. These protocols could successfully predict respectively 20.0 and 23.6 % of the HIV integrase binders, all of them being present in the LEDGF site. When a different analysis of the results was carried out by removing all alternate isomers of binders from the set, our predictions were dramatically improved, with an overall ROC AUC of 0.73 and enrichment factor at 10 % of 2.89 for the prediction obtained using Gold ChemScore. This study highlighted the ability of the selected docking protocols to correctly position in most cases the ortho-alkoxy-carboxylate core functional group of the ligands in the corresponding binding site, but also their difficulties to correctly rank the docking poses.     

Microwave assisted organic synthesis (MAOS) of small molecules as potential HIV-1 integrase inhibitors

Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). In recent years our research group has been engaged in the stucture-function study of this enzyme and in the development of some three-dimensional pharmacophore models which have led to the identification of a large series of potent HIV-1 integrase strand-transfer inhibitors (INSTIs) bearing an indole core. To gain a better understanding of the structure-activity relationships (SARs), herein we report the design and microwave-assisted synthesis of a novel series of 1-H-benzylindole derivatives.