HIV-1 protease inhibitors in development

Several pharmaceutical companies have developed an increasing number of second generation protease inhibitors (PI) during the last few years. Many of these compounds have been in preclinical trials and some are now in clinical use. All drugs in this category have been designed to be well absorbed and overcome the crucial problem of cross-resistance within this class of compounds. Taking into account the rapid occurrence of PI cross-resistance, clinicians who are treating patients with the HIV-1 infection will need new active PIs in the near future. The clinical and antiviral efficacy of the new molecules versus the older PIs will be investigated through comparative trials that are likely to be completed over the next 12 months. These third-generation PIs currently in development will be the subject of our review.     

HIV-1融合抑制剂研究现状及发展趋势

HIV-1融合抑制剂是继逆转录酶和蛋白酶抑制剂后的新一类抗HIV感染药物, 通过阻断病毒与靶细胞膜的融合从而抑制病毒进入靶细胞, 在感染的初始环节切断HIV-1的传播, 其中多肽类融合抑制剂T-20已于2003年上市。HIV-1融合抑制剂以HIV-1跨膜糖蛋白gp41为作用靶标, 它们是一些天然或合成的多肽以及小分子化合物, 通过与gp41功能区结合从而抑制其促融合功能的发挥。近年来, 随着对膜融合过程分子机制以及gp41功能研究的不断深入, 新的以gp41不同功能区为靶点的融合抑制剂分子不断被发现, 成为倍受关注的研究热点之一。本文着重对近年来HIV-1融合抑制剂的研究现状及发展趋势进行综述。     

HIV.1的转录因子NF-kB及其抑制剂的研究进展

在病毒复制循环过程中,HIV-1的转录是其中的关键步骤,可作为HIV-1治疗的新靶点.在此过程涉及的所有因子中,细胞核因子κB(nuclear factor kappa B,NF-κB)是HIV-1转录过程中重要的诱导剂.NF-κB通过与HIV-1的长末端重复序列(long terminal repeat,LTR)增强子区的连接来激活HIV-1的转录.许多化合物通过抑制NF-κB的活性来抑制HIV-1的转录.本文综述了NF-κB对HIV-1转录过程的调节及当前NF-κB抑制剂的研究进展.     

HIV-1多聚酶的结构功能及其抑制剂的研究进展

逆转录和复制是HIV-1生命周期的重要阶段,其中在多聚酶指导下的脱氧核苷酸的聚合过程是该阶段中尤为重要的一步反应,以HIV-1多聚酶为靶点的新型抗艾滋病药物的设计研究已成为该领域研究的一个新颖的热点课题.该文对HIV-1多聚酶的结构功能及近年来以此为靶点的抑制剂的研究进展进行了综述.     

新型HIV-1 非核苷类逆转录酶抑制剂的结合模式特征与抗耐药抑制剂设计研究进展

新一代抗耐药的 HIV-1 非核苷类逆转录酶抑制剂(NNRTIs)具有较高的柔韧性,能与氨基酸主链形成氢键作用,它能特异性靶向结合位点的保守性区域,且结合模式独特,属于缓慢-紧密型抑制剂。该文综述了新一代HIV-1 NNRTIs的结合模式特征,为新型抗耐药抑制剂的设计提供有价值的参考。     

HIV-1 regulatory proteins: targets for novel drug development

Due to the development of HIV-1 resistance to current antiviral drugs and the known toxicity of many of these drugs, there is a clear need to identify and develop novel compounds for use in the treatment of HIV-1 infected patients. The HIV-1 regulatory proteins, Tat and Rev, are required for HIV-1 replication and therefore represent two important viral targets for drug development. Novel drugs that target these proteins would increase the number of available treatment strategies for HIV-1 infection. This could result in better combination therapies in which many different viral targets could be inhibited simultaneously, thereby decreasing the likelihood of selecting for drug-resistant viruses. This review outlines many of the ways that Tat and Rev can be targeted for drug development, describes recently reported lead compounds as inhibitors of these proteins and discusses strategies for implementing drug screens for identifying novel inhibitors.     

HIV-1核衣壳蛋白NCp7抑制剂体外筛选方法的建立

目的表达HIV-1核衣壳蛋白(nucleocapside proteinp7,NCp7),并建立抑制剂筛选方法。方法从pBRU2/ADP202质粒经PCR得到HIV-1NCp7编码序列,克隆到pet28a质粒中构建HIV-1NCp7表达载体。阳性克隆转染E.coliBL21DE3,以IPTG诱导,细胞裂解液经Q SepharoseH.P和SP Sepharose H.P纯化后纯度达到90%以上。将具有锌离子逐出活性的H2O2和2,2′-联硫基二吡啶(2,2′-di-thiodipyridine,AT-2)与NCp7作用,用锌离子特异的荧光染料检测。用该方法检测KIZ-CM系列化合物。结果可以检测H2O2和AT-2的锌离子逐出活性,经该方法筛选,KIZ-CM10,18,19等化合物具有一定的锌离子逐出活性。结论在国内首次建立了HIV-1NCp7锌离子逐出方法,该方法可以用于NCp7抑制剂的筛选。     

二芳基嘧啶类HIV-1非核苷类逆转录酶抑制剂研究进展

2008年FDA批准上市的新一代非核苷类逆转录酶抑制剂Etravirine (TMC125) 和Ⅲ期临床候选药Rilpivirine (TMC278) 都是二芳基嘧啶 (DAPY) 类化合物, 均对HIV野生型和多种耐药性病毒株有相当强的抑制作用。DAPY类药物的发现和发展是多学科合作研发新药的成功范例。本文综述了新一代HIV非核苷类逆转录酶抑制剂DAPY类化合物的发现、发展及最新研究进展。     

Survival of HIV-1 in Syringes: Effects of Temperature during Storage

In a previous paper we demonstrated that HIV-1 survival in syringes was strongly associated with the volume of blood remaining and with the duration of storage at room temperature. The current study was performed to determine the effects of storage temperature upon the survival of HIV-1 inside syringes. At 4°C, 50% of all syringes contained viable HIV-1 at 42 days of storage, the longest storage duration tested. At room temperature (20°C), the last day that syringes with 2 μl of infected blood were positive was Day 21, and viable HIV-1 was recovered from 8% of syringes. The last day on which syringes with 20 μl were positive was Day 42, and viable HIV-1 was recovered from 8% of syringes. Above room temperature (27, 32, and 37°C), the likelihood of encountering syringes with viable HIV-1 when periods of storage exceeded 1 week decreased to less than 1%. The temperatures at which drug injectors are likely to store their used syringes will vary according to climate, season, and circumstances faced by the injector. The survival OF HIV-1 in contaminated syringes varied over a range of temperatures, and this may be a factor influencing the syringe-borne transmission of HIV-1.     

Patented small molecule inhibitors of HIV-1 integrase: a 10-year saga

Validation of integrase as a suitable therapeutic target for the development of drugs against HIV infection; discovery of diketo acid derivatives as bona fide inhibitors of integrase and the recent news of Phase II clinical trials with S-1360 are major findings fuelling the recent surge of interest in the development of integrase inhibitors. Herein, the first review of the entire patent literature for small molecule intergrase inhibitors is presented. The emphasis is based on compounds with potential to serve as leads, therefore, no attempts are made to include: antibodies, oligonucleotides or polypeptides.     

Targeting metabolic inflammation in Parkinson's disease: implications for prospective therapeutic strategies

1. Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the aetiology of PD has not been clarified as yet, it is believed that ageing, diet, diabetes and adiposity are associated with PD. 2. Type 2 diabetes and lipid abnormalities share multiple common pathophysiological mechanisms with PD. In particular, inflammation plays a critical role in the destruction of both pancreatic islet β-cells and dopaminergic neurons in the substantia nigra. Emerging evidence indicates that dysfunctions of energy metabolism evoke metabolic inflammation, which differs to the narrow concept of inflammation, participating in systemic pathological processes such as neurodegenerative disease and diabetes. 3. The brain is considered an immunologically privileged organ, free from immune reactions, because it is protected by the blood-brain barrier (BBB). However, studies have shown that there is gradual impairment of neurovascular function with ageing and in neurodegenerative disorders, resulting in abnormal states, including increased BBB permeability. Consequently, harmful elements that would not normally be able to cross the BBB, such as pro-inflammatory factors, reactive oxygen species and neurotoxins, infiltrate into the brain, triggering neural injury. 4. Currently, the drugs available for the treatment of PD only ameliorate the symptoms of the disease. Therapeutic strategies aimed at stopping or modifying disease progression are still being sought. Most recent studies suggest that both central and peripheral inflammation may be dysregulated in PD. Therefore, therapeutic strategies aimed at modulating systemic inflammatory reactions or energy metabolism may represent a goal in neuroprotection in PD.     

结构蛋白Gag及其相关基因 (蛋白) 在HIV-1晚期复制的作用及其抑制剂

人免疫缺陷病毒1型 (human immunodeficiency virus type 1, HIV-1) 复制的晚期阶段是整个复制周期中的关键环节。该阶段HIV-1经装配、出芽释放和成熟过程产生能感染新靶细胞的成熟病毒颗粒。结构蛋白Gag及其相关基因 (蛋白) 在此阶段发挥着重要作用, 它通过协同自身不同区域, 有利于蛋白质-蛋白质、蛋白质- RNA和蛋白质-脂质相互作用, 从而促进成熟感染病毒颗粒的产生。针对此阶段设计的药物, 可有效地阻断HIV-1成熟, 从而抑制病毒感染。本文综述了结构蛋白Gag及其相关基因 (蛋白) 在HIV-1晚期复制的作用及其抑制剂的研究进展。