Investigation of formation of dimeric G-quadruplex of HIV-1 integrase inhibitor by nuclear magnetic resonance

In this research, an unusually dimeric G-quadruplex of d（GGGTGGGTGGGTGGGT） （SI）, the potent nanomolar HIV-1 integrase inhibitor, was detected by nuclear magnetic resonance （NMR）. This result has been confirmed by electrospray ionization mass spectrometry （ESI-MS） and circular dichroism （CD）.

Increasing Deaths Due to Malignancy in HIV＋ Patients is Associated with Integrase Inhibitor Therapy

Despite reductions in AIDS-related deaths, registries show HIV＋ patients are still dying at a younger age than HIV-peers. Although overall mortality has declined in this population, a growing percent of deaths are due to malignancy. Since the data demonstrating the growing percentage of deaths due to malignancy in the HIV＋ population is derived from registries, the study explores whether the subset dying from malignancy has particular characteristics that can be seen in a well-characterized cohort. In the well-characterized HIV＋ cohort, the percentage of deaths due to cancer was seen to increase over four years （2010-2013） from 21% to 24% to 38% to 40%. The mean CD4-count of those who died from malignancy was 252＋/-42 and 333＋/-36 in patients with death from other causes. The viral load was not suppressed in 26% of patients dying from malignancy. Of patients on integrase inhibitor therapy, 48% of deaths were due to malignancy while in patients not on this therapy, 10% of deaths were due to malignancy （relative risk = 4.8）. In HIV＋ patients, a low CD4-count, failure to achieve viral suppression, and use of integrase inhibitors were associated with malignancy as the cause of death. The association of a specific therapy, integrase inhibition, with malignancy is seen in the study.

Design, Synthesis and Cu^2＋ Recognition of β-Diketoacid and Quinoxalone Derivatives Bearing Caffeoyl or Galloyl Moieties Linked by Arylamide as Potential HIV Integrase Inhibitors

An efficient procedure for the synthesis of caffeoyl- and galloyl-containing β-diketoacid derivatives linked by arylamide was reported by, in the key step, dissolving the corresponding phenyl methyl ketone in THF/DME in the presence of NaOMe as base and dimethyl oxalate as oxalylation reagent, and then separating the sodium ketoenolate ester. The resulting β-diketoacids underwent further condensation reaction with o-phenylenediamine to generate quinoxalone derivatives in good yield, rather than 2-benzimidazol. The preliminary ion binding properties of quinoxalone derivatives were also investigated. UV-Vis spectra showed that these compounds could selectively recognize Cu^2 ＋ ion in ethanol and form a 1 ： 2 complex.

Building the Pharmacophore Model of HIV-1 Integrase Strand Transfer Inhibitors and Studying Their Inhibition Mechanism

The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase （IN）, which includes two important reactions, 3＇-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors （INSTIs）. Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2＋ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.

The differential effects of integrase strand transfer inhibitors and efavirenz on neuropsychiatric conditions and brain imaging in HIV-positive men who have sex with men

Integrase strand transfer inhibitors(INSTIs)have emerged as the first‐line choice for treating human immunodeficiency virus(HIV)infection due to their superior efficacy and safety.However,the impact of INSTIs on the development of neuropsychiatric conditions in people living with HIV(PLWH)is not fully understood due to limited data.In this study,we conducted a cross‐sectional examination of PLWH receiving antiretroviral therapy,with a specific focus on HIV‐positive men who have sex with men(MSM)on INSTI‐based regimens(n=61)and efavirenz(EFV)‐based regimens(n=28).Participants underwent comprehensive neuropsychiatric evaluations and multimodal magnetic resonance imaging(MRI)scans,including T1‐weighted images and resting‐state functional MRI.Compared to the EFV group,the INSTI group exhibited primarily reduced gray matter volume(GMV)in the right superior parietal gyrus,higher regional homogeneity(ReHo)in the left postcentral gyrus,lower ReHo in the right orbital part of the inferior frontal gyrus,and increased voxel‐wise functional connectivity for the seed region in the left inferior temporal gyrus with clusters in the right cuneus.Furthermore,the analysis revealed a main effect of antiretroviral drugs on GMV changes,but no main effect of neuropsychiatric disorders or their interaction.The repeated analysis of participants who did not switch regimens confirmed the GMV changes in the INSTI group,validating the initial findings.Our study demonstrated gray matter atrophy and functional brain changes in PLWH on INSTI‐based regimens compared to those on EFV‐based regimens.These neuroimaging results provide valuable insights into the characteristics of brain network modifications in PLWH receiving INSTI‐based regimens。

作用于gp41的HIV融合抑制剂高通量筛选方法的研究

目的 对作用于gp4 1的HIV融合抑制剂筛选方法进行研究和改进 ,使其成为更加简便的高通量药物筛选模型。方法 采用夹心ELISA方法 ,检测HIVgp4 1六股α 螺旋束的形成。结果 以特异性识别HIVgp4 1六股α 螺旋束的单克隆和多克隆抗体为基础建立的改良夹心ELISA方法 ,特异性好 ,准确性高 ,更为简便和经济 ,能稳定有效地检测样品对 gp4 1六股α 螺旋束形成的抑制作用。 结论 本研究建立的改良方法可作为高通量药物筛选方法 ,用于从中草药库、噬菌体肽库和微生物发酵液等复杂组分样品中筛选作用于 gp4 1的HIV融合抑制剂 。

HIV-1整合酶抑制剂的研究进展

HIV-1整合酶(integrase)是逆转录病毒复制所必需的酶,因而成为抗艾滋病(AIDS)药物设计的一个合理的靶点。本文综述了近几年的HIV-1整合酶及其抑制剂的发展现状,就如何将作用于整合酶靶点的先导化合物转变成有效的抗艾滋病药物进行了讨论。

多羟基芳香族化合物对HIV-1整合酶的抑制作用

目的 研究HIV 1整合酶抑制剂 ,为艾滋病的治疗提供新作用靶位的抗HIV药物。方法 用HIV 1整合酶ELISA法检测 3种萘醌类化合物 ,10种白藜芦醇及其衍生物和 7种吡喃香豆素类化合物对整合酶的抑制作用。结果 双羟基 1,4 萘醌 (NQ 2 )对HIV 1整合酶有抑制活性 ,IC50 为 78 5 μmol·L- 1 ,发现萘醌类新化合物NQ 3对HIV 1整合酶的抑制作用优于NQ 2 ,IC50 为 3 7 2 μmol·L- 1 。用分步测定法发现NQ 2主要抑制HIV 1整合酶的链转移活性 ,而NQ 3则对装配和链转移都有较强的抑制。结论 萘醌类化合物 (NQ 2 ,3 )对HIV 1整合酶有抑制作用 ,NQ

HIV-1整合酶抑制剂体外筛选方法研究进展

整合酶是HIV基因表达和复制所必需的酶,而且宿主细胞内不存在该酶的类似物。因此,HIV-1整合酶已成为设计、筛选抗HIV药物的理想靶点。迄今为止,Raltegravir仍是唯一上市的HIV整合酶抑制剂,而且临床上也已经出现耐药问题。研发新一代整合酶抑制剂非常必要。高通量、高灵敏度、简单易行的筛选方法是研究开发新一代HIV-1整合酶抑制剂的关键。目前,HIV-1整合酶抑制剂筛选方法有多种,各有优缺点,该文将对文献报道的整合酶抑制剂体外筛选方法的最新进展做一介绍。

Inhibitors of HIV-1 Integrase-Human LEDGF/p75 Interaction Identified from Natural Products via Virtual Screening

HIV-1 integrase （IN）-mediated integration of viral DNA into the host chromosome is an essential step in the virus life cycle. Human lens epithelium-derived growth factor （LEDGF/p75） has been found to function as a cellu- lar cofactor in this process. The LEDGF/p75-1N interaction hence represents an attractive target for anti-HIV ther- apy. In this study, natural products were virtually screened against the LEDGF/p75 binding pocket of HIV-1 IN. 24 compounds were selected and obtained from the National Compound Resource Center of China. AlphaScreen as- says characterized 8 of these 24 natural products as potent LEDGF/p75-IN interaction inhibitors. The active com- pounds whose ICs0 values ranged from 0.56 to 14.55 ~mol/L could be used as lead compounds for further investi- gation. This work confirmed that natural products are valuable resources for antiviral drug discovery.

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。

中药化学数据库中HIVRT(NNRTI)/IN双靶点抑制剂的虚拟筛选

[目的]从天然产物中筛选人类免疫缺陷病毒(HIV)非核苷类逆转录酶抑制剂(NNRTI)和整合酶链转移抑制剂(INSTI)作用位点的双靶点抑制剂[RT(NNRTI)/IN]。[方法]运用分子模拟技术和计算机辅助药物设计(CADD)方法,构建HIV RT(NNRTI)/IN双靶点抑制剂分子相似性搜索模型、NNRTI和RT以及INSTI和IN对接模型,采用两种策略对中药化学数据库(TCMD)进行筛选。[结果]共命中与RT和IN对接得分均大于6的化合物35个,包括黄酮类、生物碱类、苷类、多酚类等,黄酮类化合物(15个)占到了42.86%。[结论]黄酮类化合物是开发潜在HIV RT(NNRTI)/IN双靶点抑制剂的主要来源,上述研究为天然产物来源的HIV双靶点药物发现提供了新线索。

咖啡酸衍生物的合成及其抑制HIV整合酶活性

目的合成新型咖啡酸衍生物并测定其抑制HIV 1整合酶活性。方法化学合成一系列N 取代咖啡酰萘磺胺类化合物,采用3 2 P标记法体外测定化合物抑制HIV 1整合酶活性。结果合成了2 0个咖啡酸衍生物,其结构经红外光谱、核磁共振氢谱及质谱确定。其中化合物Ⅰ2 、Ⅰ3 、Ⅰ4抑制HIV 1整合酶活性高于L 巨菊酸(IC50 =11 8μg·mL-1) ,3个化合物的IC50 分别为(8 .6±4 . 8)、(4. 5±3 .4 )、(7 .9±4 . 9) μg·mL-1。结论N 取代咖啡酰萘磺胺类化合物对HIV 1整合酶有较高抑制活性,值得深入研究。

HIV-1整合酶3′端加工抑制剂筛选方法的建立与优化

目的建立与优化HIV-1整合酶3'端加工抑制剂筛选方法。方法利用荧光共振能量转移原理建立筛选方法,用DNaseⅠ切割底物DNA确定底物检测波长,在该检测波长下,对缓冲液成分、底物浓度、酶浓度、金属离子浓度等影响整合酶活性的条件进行优化,并用阳性药物雷特格韦和杨梅黄素进行方法验证。结果检测波长为495 nm/525 nm,使用缓冲液1、底物浓度500 nmol·L-1,整合酶浓度1μmol·L-1,镁离子浓度20 mmol·L-1时整合酶3'端加工活性最强。在此反应条件下雷特格韦和杨梅黄素能有效地抑制整合酶3'端加工活性。用所建立的方法筛选到2个有较强抑制整合酶3'端加工活性的抑制剂。结论该文成功建立并优化了HIV-1整合酶3'端加工抑制剂筛选方法。

HIV整合酶抑制剂体外筛选方法研究进展

为了评价HIV整合酶抑制剂体外筛选方法的特点和整合酶抑制剂研究进展,以常用的3′加工反应法、链转移反应法、改良ELISA法及基于结构的筛选为基础归类整合酶抑制剂。整合酶抑制剂按方法分为五类,并可推测其作用机制,通过比较可知以上方法各有利弊,需配合运用。整合酶抑制剂有研究价值。

HIV-1整合酶抑制剂的研究进展

HIV-1整合酶是设计抗艾滋病药物的理想靶点,综述了HIV-1整合酶抑制剂的研究进展。

双二酮酸结构HIV-1整合酶抑制剂的合成及活性研究

目的设计合成双二酮酸类化合物,并探讨此类化合物抑制HIV-1整合酶活性的构效关系。方法以甲基取代苯乙酮为起始原料,经溴代后与羟基取代苯乙酮反应生成乙酰基苄氧苯乙酮,然后在氢化钠作用下,脱去α氢后进攻草酸二乙酯生成双二酮酸酯,水解脱去酯基生成双二酮酸;经1H-NMR、IR和MS验证化合物结构。ELISA法测定目标化合物对HIV-1整合酶的抑制活性;采用高通量荧光法测定目标化合物对HIV-1整合酶3'加工过程的抑制活性;测定目标化合物对HIV假病毒的细胞活性。结果合成了6个全新结构的二酮酸类化合物;体外整合酶活性评价结果表明,6个目标化合物对HIV-1整合酶的活性IC50≤20μg/ml,双二酮酸之间距离稍短的5a、5c、5d对3'加工过程有一定的活性,IC50约为40μg/ml。结论 6个新化合物对HIV-1的活性主要表现在链转移过程。

基于结构的HIV-1整合酶抑制剂设计:计算机模拟方法

HIV整合酶是一种病毒编码蛋白质 ,它催化病毒DNA整合进入宿主基因组 ,这为开发新的抗HIV和抗艾滋病疗法提供了一个重要的靶标。综述通过计算机模拟方法进行基于结构的HIV 1整合酶抑制剂设计 ,内容包括基于配体 (如药效团 )和基于靶向 (如对接 )的设计方法以及三维定量构效关系研究。

不同抗病毒治疗方案对HIV病毒库的影响

目的随着抗逆转录病毒疗法(antiretroviral therapy,ART)的进步,使艾滋病(acquired immune deficiency syndrome,AIDS)从一种致死性疾病转化为可治疗的慢性感染性疾病。通过前瞻性队列研究,掌握整合酶抑制剂(integrase inhibitors,INSTI)时代不同ART方案降低人类免疫缺陷病毒1型(human immunodeficiency virus-1,HIV-1)DNA速率的特征和结局,探索最佳治疗模型。方法选取2020年9月—2022年8月重庆市公共卫生医疗救治中心招募的HIV感染者,采用前瞻性队列研究方法,实时PCR对外周血单个核细胞(peripheral blood mononuclear cell,PBMC)中的总HIV-1 DNA进行定量,这些PBMC采集自744例初治及经治感染者,分为四组同时进行临床观察:第一组初治,第3种药物为非核苷类反转录酶抑制剂(non-nucleoside reverse transcriptase inhibitors,NNRTI)。第二组初治,第3种药物为INSTI。第三组经治,继续原方案使用NNRTI。第四组经治,由NNRTI转换成INSTI。在治疗前(0周)及治疗后每3个月(3、6、9、12、15、18、21、24个月),检测病毒载量(HIV-1 RNA)、CD4^(+)T淋巴细胞(CD4^(+)T lymphocyte,CD4^(+))、CD4^(+)/CD8^(+)T淋巴细胞(CD8^(+)T lymphocyte,CD8^(+))比值及HIV-1 DNA定量水平。观察不同治疗方案HIV-1 DNA下降速率及HIV-1 DNA水平是否有差异。结果初治HIV感染者只要采用规范的抗病毒治疗方案,无论是INSTI联合治疗方案或NNRTI联合治疗方案,HIV-1 DNA均获得有效降低,INSTI治疗组的HIV-1 DNA减少较NNRTI治疗组更明显。经治HIV感染者,不管继续原方案或转换成INSTI,HIV-1 DNA量未发现差异。结论HIV-1 DNA水平是初治患者治疗方案评估的新指标;最新一代药物,如INSTI可能是治疗HIV感染的最佳选择。