小分子CCR5拮抗剂研究进展

趋化因子受体5(CCR5)是HIV-1侵入宿主细胞的主要辅助受体之一.目前已发现许多小分子CCR5拮抗剂,其中一些化合物已进入临床研究和应用.本文介绍了小分子CCR5拮抗剂的作用机制,综述了近几年来各种不同结构类型的小分子CCR5拮抗剂的研究进展.     

CCR5小分子拮抗剂类抗艾滋病药物研究进展

趋化因子受体CCR5是抗艾滋病药物作用的重要靶点之一。目前，已经开发了许多活性强、选择性高的CCR5拮抗剂，其中一部分已进入临床试验阶段。本文对近年来文献报道的CCR5小分子拮抗剂进行综述。     

单克隆抗体HIV进入抑制剂PRO140

HIV病毒株可分为R5嗜性和X4嗜性,它们分别通过趋化因子CCR5和CXCR4辅助受体进入CD4细胞。在HIV的整个发展进程中,可常发生其病毒株由R5嗜性转型为X4嗜性,且也有可能某个体同时被R5嗜性和X4嗜性病毒感染,而CCR5拮抗剂则对x4嗜性病毒无效。由Progenics制药公司开发的用于治疗HIV感染的人源化单克隆抗体CCR5拮抗剂PRO140为一种新型HIV进人抑制剂,可与CCR5受体的特殊区段紧密结合,对CCR5产生拮抗作用,从而抑制HIV通过这一辅助受体进入靶细胞;     

小分子趋化因子受体4拮抗剂研究进展

CC类人类趋化因子受体4(CCR4)是趋化因子家族中具有7个跨膜结构的G蛋白偶联受体。CCR4受体与自身免疫性疾病、哮喘、特应性皮炎等多种疾病的形成和发展有关,可成为这些疾病新的治疗靶点,受到越来越多学者的关注。CCR4拮抗剂的研究成为研发治疗上述疾病药物新热点。本文对近年来小分子CCR4拮抗剂的研究进展进行综述。     

HIV-共受体CCR5的三维结构及与其拮抗剂TAK 779相互作用的比较分子模拟(英文)

目的:研究HIV-1的共受体CCR5与其拮抗剂TAK779的相互作用机制。方法:用比较分子模拟方法建立CCR5受体的三维结构模型;通过量子化学计算得到TAK779分子的结构参数和最优几何构型;用DOCK4.0程序将TAJ779分子对接到CCR5受体的结合位点上。结果:通过分子力学优化得到了CCR5受体的三维结构模型,配体的结合口袋位于第三、五、六、七跨膜区,组成结合口袋的氨基酸残基主要为Thr105、Leu107、Tyr108、Gly111、Phe112、Ser114、Gly115、Lys197、Glu283、Gly286、Met287、Cys290;TAK779与CCR5受体的相互作用方式为氢键、静电和疏水作用;配体与受体的结合能为-51.606 kcal/mol。结论:上述模型有助于进一步理解膜受体识别HIV-1病毒的分子机制并设计新的HIV-1抑制剂。     

CCR5阻滞剂马拉韦罗的药理与临床评价

马拉韦罗是一种选择性、可逆的小分子抑制剂,能与细胞膜表面人化学趋化因子受体-5(CCR5)和HIV-1gp120相互作用,抑制CCR5-tropic HIV-1病毒进入细胞,是一种很有前途的新型抗病毒药.现对其药理作用、药动学、药物相互作用及对仅感染CCR5-tropic HIV-1的成年患者的疗效和安全性进行了综述.     

补体C5a、C5a受体及其拮抗剂的研究进展

C5a是最重要的补体活化产物之一,它与相应的C5a受体结合被激活后,参与了多种疾病的病理过程,如急性肺损伤、脓毒血症、类风湿性关节炎、肾小球肾炎等疾病。如何阻断C5a信号的下传,从而减轻炎症反应一直是免疫学研究的热点问题。目前C5a和C5a受体的拮抗剂主要分为抗C5a抗体、小分子拮抗剂、C5a反义肽、C5a突变体和细菌来源的趋化抑制蛋白等。本文着重介绍C5a和C5a受体的结构与功能,以及相关拮抗剂的研究进展。     

抗HIV药物靶点CCR5及HIV对CCR5抑制剂的抗性

趋化因子受体CCR5是细胞膜表面G蛋白偶联受体中的一员.HIV-1在体内与细胞融合时需要CCR5作为辅助受体介导.因此,CCR5可作为抗HIV-1药物的筛选靶点,目前已筛选出多种CCR5抑制剂.但随着CCR5抑制剂的使用,HIV-1对于这些抑制剂的抗性也逐渐产生,而抗性的产生机制还不明确.本文主要介绍CCR5介导HIV-1与细胞融合的机制及HIV-1对CCR5抑制剂的抗性产生机制.     

抗艾滋病药Vicriviroc

Vicriviroc是先灵葆雅公司正在开发的抗HIV感染药,属于一种小分子的趋化因子受体CCR5拮抗剂,能显著抑制HIV-1进入宿主细胞,可与其它药物联合使用治疗嗜R5型HIV-1感染的病人。已有临床试验结果表明,在采用优化基础疗法（如利托那韦加另一种蛋白酶抑制剂）的同时使用vicriviroc（10mg,qd）,能明显降低艾滋病患者体内的HIV病毒载量,并增加其CD4＋细胞数量。目前,本品尚处Ⅱ／Ⅲ期临床研究阶段。     

以趋化因子受体为靶点的抗HIV药物研究进展

趋化因子受体是HIV进入宿主细胞的共受体,特别是CCR5和CXCR4在HIV进入免疫细胞过程中起着重要作用。以趋化因子受体为靶点的新型抗艾滋病药物的设计与开发已成为抗艾滋病领域研究的一个热点课题。本文对近期抗HIV-1趋化因子受体(CCR5和CXCR4)拮抗剂的研究进展进行综述。     

Discovery of a Potent and Orally Bioavailable CCR2 and CCR5 Dual Antagonist

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CCR5 inhibitors: emergence,success, and challenges

Introduction: The discovery of CC-chemokine receptor 5 (CCR5) as a human immunodeficiency virus type 1 (HIV-1) coreceptor opened a new avenue to exploit CCR5 as a potential target for the intervention of HIV-1's cellular entry.

Areas covered: Various small-molecule CCR5 inhibitors were identified in the last decade; however, maraviroc (MVC) is the only CCR5 inhibitor currently used in the clinic. Concerns and challenges that exist for wider clinical use of CCR5 inhibitors are discussed.

Expert opinion: Although MVC-containing regimens have been recommended for treatment-naïve patients, MVC appears to have been used as one of drugs for salvage therapy rather than for treating drug-naïve patients. This is apparently due to MVC's twice-daily dosing schedule. Another significant disadvantage is that a costly tropism assay must be performed prior to MVC treatment. The access to inexpensive, sensitive, and rapid tropism tests should be made easily available. Only a few novel CCR5 inhibitors are presently in the pipeline. Development of potent and metabolically-stable novel CCR5 inhibitors allowing once-daily dosing regimens is needed. Development of CXCR4 inhibitors should greatly improve the treatment options available to patients infected with X4- and/or dual-tropic HIV-1 strains in combination with a CCR5 inhibitor.     

Oral CCR5 inhibitors: will they make it through?

The therapeutic armamentarium against HIV has recently gained a drug belonging to a novel class of antiretrovirals, the entry inhibitors. The last decade has driven an in-depth knowledge of the HIV entry process, unravelling the multiple engagements of the HIV envelope proteins with the cellular receptorial complex that is composed of a primary receptor (CD4) and a co-receptor (CCR5 or CXCR4). The vast majority of HIV-infected subjects exhibit biological viral variants that use CCR5 as a co-receptor. Individuals with a mutated CCR5 gene, both homo- and heterozygotes, appear to be healthy. For these and other reasons, CCR5 represents an appealing target for treatment intervention, although certain challenges can not be ignored. Promising small-molecule, orally bioavailable CCR5 antagonists are under development for the treatment of HIV-1 infection.     

CCR5基因启动子多态性与2型糖尿病肾病相关性研究

目的 探讨趋化因子受体5(CCR5)基因启动子多态性与中国人2型糖尿病肾病之间的关系.方法 应用聚合酶链反应限制性片段长度多态性技术(PCR-RFLP),检测2型糖尿病患者、2型糖尿病合并肾病患者及正常对照组CCR5基因启动子59029G/A基因型,并对各组间的等位基因频率与基因型频率进行比较. 结果 A( )基因型:单纯糖尿病组(DNO)与糖尿病肾病微量白蛋白尿组(DN1)比较差异有显著性(P=0.310),与大量白蛋白尿组(DN2)比较差异有显著性(P＜0.01),DN1组与DN2组比较差异有显著性(P=0.002),DNO组与糖尿病肾病组(DN1 DN2)比较差异有显著性(P=0.007).结论 CCR5 59029G/A基因多态性与糖尿病肾病的发展密切相关.     

苦参素对实验性自身免疫性脑脊髓炎大鼠CCL5、CCR5及CCR5mRNA表达的影响

目的:观察苦参素对实验性自身免疫性脑脊髓炎(EAE)大鼠血清中趋化因子CCL5和脊髓中趋化因子CCL5相应的受体(CCR5)及CCR5mRNA表达的影响,探讨苦参素对EAE大鼠的防治机制。方法:用豚鼠全脊髓匀浆和完全弗氏佐剂混合制成抗原乳剂,诱导EAE模型,将40只Wistar大鼠随机分为正常组、模型组、苦参素低剂量组(150mg·kg^-1)、苦参素高剂量组(250mg·kg^-1),苦参素高、低剂量组均连续腹腔给药16d,同期正常组和模型组腹腔注射等量生理盐水,观察大鼠体质量变化,神经功能学评分,进行HE及C-2R-BG病理染色,用ELISA法测定大鼠血清中CCL5的含量、免疫组化法检测大鼠脊髓组织中CCR5的阳性表达、RT-PCR法检测脊髓中CCR5mRNA的表达。结果:苦参素高、低剂量组大鼠的体质量均高于模型组(P<0.05),神经功能学评分,炎症浸润和髓鞘脱失评分,血清中CCL5的水平,脊髓中CCR5、CCR5mRNA的表达均低于模型组(P<0.05),且高低剂量组有组间差异(P<0.05)。结论:苦参素对EAE大鼠具有一定的防治作用,其作用机制可能与下调大鼠CCL5、CCR5及CCR5mRNA的表达有关。     

Chemokine receptor CCR5: from AIDS to atherosclerosis

There is increasing recognition of an important contribution of chemokines and their receptors in the pathology of atherosclerosis and related cardiovascular disease. The chemokine receptor CCR5 was initially known for its role as a co-receptor for HIV infection of macrophages and is the target of the recently approved CCR5 antagonist maraviroc. However, evidence is now emerging supporting a role for CCR5 and its ligands CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) in the initiation and progression of atherosclerosis. Specifically, the CCR5 deletion polymorphism CCR5delta32, which confers resistance to HIV infection, has been associated with a reduced risk of cardiovascular disease and both CCR5 antagonism and gene deletion reduce atherosclerosis in mouse models of the disease. Antagonism of CCL5 has also been shown to reduce atherosclerotic burden in these animal models. Crucially, CCR5 and its ligands CCL3, CCL4 and CCL5 have been identified in human and mouse vasculature and have been detected in human atherosclerotic plaque. Not unexpectedly, CC chemokines have also been linked to saphenous vein graft disease, which shares similarity to native vessel atherosclerosis. Distinct roles for chemokine-receptor systems in atherogenesis have been proposed, with CCR5 likely to be critical in recruitment of monocytes to developing plaques. With an increased burden of cardiovascular disease observed in HIV-infected individuals, the potential cardiovascular-protective effects of drugs that target the CCR5 receptor warrant greater attention. The availability of clinically validated antagonists such as maraviroc currently provides an advantage for targeting of CCR5 over other chemokine receptors.     

A novel template for non-peptide CCR5 receptor antagonists

Potent non-peptide chemokine CCR5 receptor antagonists have been identified, based upon a 1(1-aroylpiperidin-4-yl)piperidine template previously employed in a series of muscarinic M₂ receptor antagonists. Two applications claim piperidinylpiperidine and piperidinylpiperazine derivatives, respectively, including compounds with low nanomolar affinity for the CCR5 receptor. Such compounds are claimed to be useful in the treatment of HIV infection and inflammatory diseases.     

Effect of CCR5 receptor antagonists on endocytosis of the human CCR5 receptor in CHO-K1 cells

Background and purpose:

The CCR5 chemokine receptor is a member of the G protein-coupled receptor (GPCR) family that is expressed by macrophages, memory T-lymphocytes and dendritic cells and is activated by chemotactic proteins (e.g. MIP-1α [CCL3], MIP-1β [CCL4] and RANTES [CCL5]). CCR5 is also the principal co-receptor for macrophage-tropic strains of human immunodeficiency virus-1 (HIV-1) and some chemokines can inhibit HIV-1 infection by stimulating CCR5 receptor endocytosis. The aim of this study was to evaluate the effect of CCR5 antagonists on CCR5 endocytosis.

Experimental approach:

The effects of CCR5 agonists and antagonists on receptor internalization in CHO cells, expressing a C-terminal green fluorescent protein-tagged human CCR5 receptor (CCR5-GFP), were quantified using a confocal imaging plate reader.

Key results:

MIP-1α [CCL3], MIP-1β [CCL4] and RANTES [CCL5] were all able to stimulate potently the internalization of CCR5-GFP. This effect was inhibited by the non-peptide antagonist TAK 779. The CCR5 peptide antagonist met-RANTES antagonized MIP-1α-mediated increases in intracellular free calcium but was also able to stimulate a substantial internalization of the human CCR5-GFP receptor. However, CHO cells exhibited an aminopeptidase activity that was able to metabolize sufficient met-RANTES into an agonist metabolite capable of stimulating calcium mobilization via CCR5 receptors in naïve cells.

Conclusions and implications:

These data suggest that there is an endogenous aminopeptidase activity on the surface of CHO cells, that produces a slow internalization of the receptor following a time-dependent conversion of receptor-bound met-RANTES from a CCR5 receptor antagonist into a CCR5 agonist molecule.