HIV进入抑制剂研究进展

HIV进入抑制剂主要干预病毒包膜与靶细胞膜融合过程,可有效预防HIV感染。在HIV进入细胞过程中,HIV包膜糖蛋白gp120首先与宿主细胞膜上的CD4分子结合,使gp120构型变化,继而与CCR5或CXCR5等辅助受体结合,诱使跨膜亚基gp41构型改变,HIV包膜与细胞膜空间靠近,最终融合。基于这一过程,可通过筛选与gp120结合的化合物、设计CD4模拟物、研制CD4或CCR5单抗、构建辅助受体抑制剂等方法,从各个方面干预HIV的进入。对HIV进入抑制剂的靶标和药物研发进展进行概述。

     

作用于HIV gp120的进入抑制剂研究进展

HIV-1病毒为包膜病毒,其感染靶细胞的第一步是由HIV包膜蛋白表面亚基gp120与靶细胞上的CD4分子和辅助受体（趋化因子受体CCR5或CXCR4等）结合,导致gp41的构型发生改变,启动病毒包膜与靶细胞膜的融合。与gp120相结合的一些抗体、蛋白、多糖、多肽和小分子化合物,都可能影响HIV-1病毒包膜和靶细胞膜融合的过程,从而起到抗HIV-1病毒的作用。该文对近年来以HIV gp120为靶点的HIV进入抑制剂的研究进展进行综述。     

新型抗艾滋病药物——HIV进入抑制剂的研究进展

HIV与靶细胞融合的过程是药物干预的重要环节。融合过程主要由H IV包被蛋白表面亚基gp120和跨膜亚基gp41介导。H IV gp120与靶细胞上的CD4分子和辅助受体(趋化因子受体CCR5或CXCR4等)结合,导致gp41的构型发生改变,启动病毒包膜与靶细胞膜的融合。在融合过程中,病毒和靶细胞上的这些蛋白和受体均可作为药物的作用靶点,寻找抑制H IV进入靶细胞的药物用来治疗H IV感染和艾滋病。作用于gp41的肽类药物T-20已被美国FDA批准上市,表明继逆转录酶抑制剂和蛋白酶抑制剂后,H IV进入抑制剂作为第3类抗H IV药物开始在临床上应用。作为一种新机制的抗H IV药物,H IV进入抑制剂单独或与逆转录酶抑制剂和蛋白酶抑制剂联合应用,将有助于提高药物的疗效,降低毒副作用,并可望挽救对现有抗H IV药物耐药的艾滋病病人的生命。该文综述了近年来H IV进入抑制剂的研究进展。     

HIV包膜蛋白的结构及其相应的病毒进入抑制剂

HIV-1病毒包膜蛋白gp120和gp41在病毒感染中起着重要的作用。在病毒进入细胞的过程中,gp120先和CD4分子结合,发生构象改变,进而导致gp41构象的变化,使病毒包膜和细胞膜融合而感染细胞。与gp120或者gp41相结合的多肽、大分子和小分子化合物,都可能影响HIV-1病毒包膜和靶细胞膜结合的过程,从而起到抗HIV-1病毒的作用。该文对gp120和gp41的结构及其相互作用,以及以HIV-1包膜糖蛋白为靶点的病毒进入抑制剂类抗艾滋病药物进行综述。     

人类免疫缺陷病毒进入抑制剂的临床开发与应用

耐药性是目前用抗病毒药物治疗获得性免疫缺陷综合征(艾滋病,AIDS)的主要问题。HIV进入抑制剂可以阻断HIV病毒进入人体细胞,具有新的作用机制,对其开发是目前解决耐药性问题的主要方向之一。目前国内已有多家单位在进行HIV进入抑制剂研究,有些即将进入临床试验阶段。本文结合我们自身的研究工作,着重综述了HIV进入抑制剂在预防与治疗艾滋病中的应用研究情况,特别讨论了其临床试验的目的、设计方案,以及进入抑制剂与目前药物联合使用的思路。     

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.     

酸性天然凝胶电泳法研究HIV进入抑制剂ADS-J1的作用机制

目的ADS-J1是通过虚拟筛选从20000个化合物中获得的靶向HIVgp41的小分子HIV进入抑制剂。该研究探讨ADS-J1与gp41的结合位点和作用机制。方法采用酸性天然聚丙烯酰胺凝胶电泳技术(AN-PAGE),研究ADS-J1与衍生于gp41不同功能区的多肽的结合。结果此前采用的天然聚丙烯酰胺凝胶电泳(N-PAGE)等方法,由于不能显示衍生于gp41的N-端多肽,未能确定ADS-J1的作用位点。该研究建立的AN-PAGE技术,能直接显示N-端多肽的条带,证实ADS-J1能与gp41的N-端螺旋重复序列(NHR)复合螺旋核中的深穴结合,从而抑制gp41六螺旋束结构的形成,而且深穴中第574位的赖氨酸残基(K574)与ADS-J1的抑制作用密切相关。结论ADS-J1通过与gp41 NHR靶穴中的K574结合,抑制gp41六螺旋束结构的形成,从而抑制HIV进入靶细胞。此外,该研究建立的AN-PAGE技术,为研究靶向Ⅰ型包膜病毒的病毒进入抑制剂的作用机制提供了一个简便有效的实验方法。     

新类型的抗HIV药物——CCR5拮抗剂

艾滋病是由于感染了人类免疫缺陷病毒（human immtmodeficiency virus,HIV）后引起的一种严重危害人类健康的传染病。HIV主要破坏人体的免疫系统,使机体逐渐丧失防卫能力。因而晚期艾滋病患者易受条件致病因素及肿瘤的攻击,并最终因此而死亡。临床上,目前常用的几类抗HIV药物如逆转录酶抑制剂和蛋白酶抑制剂。但长期使用不良反应较大,耐药性问题也日趋严重,迫切需要寻找新的抗HIV靶点。     

HIV蛋白酶抑制剂研究进展

艾滋病 (acquiredimmunodeficiencysyndrome,AIDS)是由人免疫缺陷病毒(humanimmunodeficiencyvirus,HIV)感染导致人体免疫机能缺陷,而易于发生机会性感染和肿瘤的临床综合征 [1]。在过去的20多年里造成2 000多万人死亡,目前全世界艾滋病病毒感染者已达4 000万左右 [2]。自     

HIV侵入抑制剂的研究进展

综述了HIV侵入抑制剂的作用机制,并阐述其在抗HIV药物研究中的进展.     

抗CD22单克隆抗体Epratuzumab

单克隆抗体疗法目前已成为治疗B细胞恶性肿瘤和自身免疫性疾病[如非霍奇金淋巴瘤（NHL）、Sjsgren综合征和系统性红斑狼疮（SLE）]的一项重大突破,而B细胞特异性免疫球蛋白CD22也已被鉴定为治疗这些疾病的靶标。分子质量为13．5万的CD22是一种跨膜唾液酸糖蛋白,属免疫球蛋白超家族成员,仅表达于分化成熟期B细胞的表面,对B细胞的生长、存活和功能起重要作用。研究显示,CD22在99％的NHL细胞中均有表达,     

Photolabeling identifies transmembrane domain 4 of CXCR4 as a T140 binding site

CXCR4, a G-protein-coupled receptor, which binds the chemokine stromal cell-derived factor 1 alpha (SDF-1α, CXCL12), is one of two co-receptors most frequently used by HIV-1 to infect CD4+ lymphocytes. The SDF-1α/CXCR4 axis is also involved in angiogenesis, in stem cell homing to bone marrow, in rheumatoid arthritis and in cancer. Here, we directly determined the binding site of the inverse agonist T140 on CXCR4 using photoaffinity labeling. Two T140 photoanalogs were synthesized containing the photoreactive amino acid p-benzoyl-l-phenylalanine (Bpa) in positions 5 or 10, yielding [Bpa⁵]T140 and [Bpa¹⁰]T140. Binding experiments on HEK293 cells stably expressing the wild-type CXCR4 receptor using ¹²⁵I-SDF-1α demonstrated that T140 and both photoanalogs had affinities in the nanomolar range, similar to SDF-1α. Photolabeling led to the formation of specific, covalent 42 kDa T140-CXCR4 complexes. V8 protease digestion of both CXCR4/¹²⁵I-[Bpa⁵]T140 and CXCR4/¹²⁵I-[Bpa¹⁰]T140 adducts generated a fragment of 6 kDa suggesting that the T140 photoanalogs labeled a fragment corresponding to Lys¹⁵⁴-Glu¹⁷⁹ of the receptor's 4th transmembrane domain. Further digestion of this 6 kDa fragment with endo Asp-N led to the generation of a shorter fragment validating the photolabeled region. Our results demonstrate that T140 interacts with residues of the fourth transmembrane domain of the CXCR4 receptor and provide new structural constraints enabling us to model the complex between T140 and CXCR4.     

Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity

Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC(50) 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC(50) 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC(50) 9 ± 4 nM, CC(50) 135 ± 7 μM, therapeutic index = 15,000).     

Glycosyl Phosphatidylinositol-Anchored C34 Peptide Derived From Human Immunodeficiency Virus Type 1 Gp41 Is a Potent Entry Inhibitor

Journal of Neuroimmune Pharmacology - Lipid rafts of the plasma membrane have been shown to be gateways for HIV-1 budding and entry. In nature, many glycosyl-phosphatidylinositol (GPI) anchored...     

Entry of oximes into the brain: a review

The passage of hydrophilic drugs, such as oxime acetylcholinesterase reactivators, into the central nervous system is restricted by the blood-brain and the blood-cerebrospinal fluid barriers. The present review summarizes morphological and functional properties of the blood-brain barrier, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain interface and reviews the existing data on brain entry of oximes. Due to the virtual absence of transcytosis, lack of fenestrations and unique properties of tight junctions in brain endothelial cells, the blood-brain barrier only allows free diffusion of small lipophilic molecules. Various carriers transport hydrophilic compounds and extrude potentially toxic xenobiotics. The blood-cerebrospinal fluid barrier is formed by the choroid plexus epithelium, whose tight junctions are more permeable than those of brain endothelial cells. The major function of plexus epithelium cells is active transport of ions for the production of the cerebrospinal fluid. The cerebrospinal fluid-brain interface is not a biological barrier and allows free diffusion. However, in contrast to passage via the blood-brain barrier or the blood-cerebrospinal fluid barrier, direct penetration from the cerebrospinal fluid into the brain is very slow, since much longer distances have to be covered. A bulk flow of brain interstitial fluid and cerebrospinal fluid speeds up exchange between these two fluid compartments. Oximes, by reactivating acetylcholinesterase, are important adjunct therapeutics in organophosphate poisoning. They are very hydrophilic and therefore cannot diffuse freely into the central nervous system. Changes in brain acetylcholinesterase activity, oxime concentration and some biological effects elicited by oxime administration in the periphery indicate, however, that oximes can gain access to the brain to a certain degree, probably by carrier-mediated transport, reaching in the brain about 4-10% of their respective plasma levels. The clinical relevance of this effect is hotly debated. Possible strategies to improve brain penetration of oximes are discussed.     

微管蛋白聚合抑制剂类抗肿瘤药Plinabulin

鉴于血管生成对肿瘤的生长和转移至关重要,因此肿瘤血管系统已成为极具价值的肿瘤治疗靶。目前,靶向肿瘤脉管系统的抗肿瘤药物主要包括抗血管生成剂和血管阻断剂（VDAs）,前者可抑制肿瘤新血管的生长,而后者则是靶向破坏为肿瘤细胞供应氧和营养的已有血管网。肿瘤血管具有与正常血管不同的异常结构,     

HIV integrase inhibitors: a new era in the treatment of HIV

Introduction: Integrase inhibitors (INIs) are the latest class of antiretroviral drugs approved for the treatment of HIV infection and are becoming ‘standard’ drugs in the treatment of both naïve as well as heavily pretreated individuals with HIV.

Areas covered: Data on efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and resistance are reviewed from the pivotal Phase III clinical trials published in PubMed high-impact medical journals or presented at international meetings.

Expert opinion: Due to their outstanding data of efficacy, tolerability, safety – shared by all three drugs (raltegravir, elvitegravir, dolutegravir) currently belonging to this new family of antiretrovirals – INIs have become part of the recommended initial antiretroviral therapy options. Some differences in dosing, drug-drug interactions and robustness/genetic barrier among the three drugs will provide the physician the characteristics to make the best choice.     

Impact of Stereochemistry on Ligand Binding: X-ray Crystallographic Analysis of an Epoxide-Based HIV Protease Inhibitor

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Solid Lipid Nanoparticles Enhance the Delivery of the HIV Protease Inhibitor, Atazanavir, by a Human Brain Endothelial Cell Line

Purpose  Protease inhibitors (PIs) exhibit low brain permeability. As a result, unchallenged HIV viral replication can lead to HIV-encephalitis and antiretroviral drug resistance. The objective of this study was to develop and evaluate a lipid nanoparticle system for enhanced brain delivery of the potent and frequently used HIV PI, atazanavir, using a well characterized human brain microvessel endothelial cell line (hCMEC/D3) representative of the blood-brain barrier. Methods  Solid lipid nanoparticles (SLNs) were prepared by a thin film hydration technique and analyzed for atazanavir encapsulation efficiency, particle size, morphology, zeta potential and drug release. Cell viability experiments demonstrate that SLNs exhibit no toxicity in hCMEC/D3 cells up to a concentration corresponding to 200 nM of atazanavir. Results  Spherical SLNs with an average particle size of ~167 nm were formulated. Delivery of [³H]-atazanavir by SLNs led to a significantly higher accumulation by the endothelial cell monolayer as compared to the drug aqueous solution. Furthermore, release of Rhodamine-123 (a fluorescent probe) by SLNs also resulted in a higher cellular accumulation. Conclusions  These data suggest that SLNs could be a promising drug delivery system to enhance brain uptake of atazanavir and potentially other PIs.