化学蛋白质组学技术在药物靶标鉴定中的应用

药物开发过程面临多重挑战,而靶标确证是其中的重要一环。如何运用多种研究方法发现和确认小分子药物的靶标是目前研究人员的主要工作内容之一。化学蛋白质组学整合了细胞生物学、合成化学和生物质谱等多门学科,为药物的靶标筛选提供了新平台。本文对近年来发展的基于生物质谱的化学蛋白质组学药物靶标鉴定技术进行了总结,结合具体应用分析其优缺点,并对该类技术的发展和应用进行总结和展望。     

药物靶标蛋白筛选的化学蛋白质组学研究进展

药物或生物活性物质通过与靶蛋白结合而发挥功能,研究表明,大多数药物具有多个作用靶点,药物靶标的发现有助于药物前体的筛选和作用机制的研究,同时对其耐药性等副作用的解决方案提供理论指导.基于生物质谱技术的蛋白质组学可对蛋白质进行高通量的定性定量分析,为药物靶标的筛选提供了全新的平台.本文综述了基于固载药物和游离药物模式的药物靶标蛋白筛选相关方法和应用研究的最新进展,为基于生物质谱技术的化学蛋白质组学研究提供参考.     

RGD三肽的潜在作用靶标预测与计算机模拟分析

化学基因组技术是药物作用靶标确认、药物分子在通路中的作用的确证等方面有重要应用,可为新药研发和老药新用提供理论依据,并可降低药物发现中的高额成本.精氨酸-甘氨酸-天冬氨酸(RGD)三肽被证明是与细胞粘附受体特异性结合的特征序列,在生理学上扮演者重要角色.本研究利用化学基因组学中的其中一种方法即基于反向对接和药效团反向匹配搜索技术来研究RGD三肽的潜在作用靶标,并进行计算机模拟分析.反向匹配搜索结果发现计算得到的关键性靶标及其涉及的相关疾病与实验报道的RGD的药理活性相吻合,包括具有抗凝血、抗肿瘤作用,与肾及心血管作用有关等,而且还发现RGD可能是一个潜在的神经氨酸酶的抑制剂.     

我国农业生物药物分子设计平台建设取得可喜进展

国家“863”计划现代农业技术领域通过攻关发现并鉴定了一系列基因和蛋白质新靶标,在农业生物药物分子设计平台建设方面取得可喜进展。     

天然活性成分作用靶点识别及确证方法的研究进展

药物靶标的发现和验证是新药研发的关键环节,对新药创制具有源头创新意义。天然产物是新药创制的重要来源,识别其作用靶点不仅为临床预防治疗提供可能新策略,也为进一步阐释中草药及其复方的作用特点及分子机制提供参考依据。随着生命科学和信息学的发展,药物靶点的识别及确证方法不断涌现,生物信息学、网络药理学、蛋白质组学、亲和色谱、药物亲和稳定性、芯片技术、基因敲除技术、RNA干扰等技术的广泛应用,越来越多的天然活性成分的靶点得以识别和验证。因此,本文对近五年来天然活性成分作用靶点识别及确证方法做一简要综述,以供参考。     

ATP竞争性mTOR抑制剂研究进展

哺乳动物雷帕霉素靶蛋白(mTOR)是一种丝氨酸/苏氨酸激酶,可集合胞内和胞外信号调节细胞生长、增殖、代谢和存活。在肿瘤的发生发展过程中,mTOR信号多处于异常激活状态,已被确证为肿瘤药物治疗的重要靶标。因雷帕霉素临床应用存在局限性,近期ATP竞争性mTOR抑制剂的研发十分活跃。本文综述了ATP竞争性mTOR抑制剂的研究进展,重点讨论药物的作用特点。     

靶向共价键药物的研究进展

药物与靶标的结合是启动药理作用的本源,共价键药物是以共享电子的方式来实现与靶标的结合,其中大多为抗感染、抗肿瘤以及心脑血管、神经系统和代谢类药物。简介共价键药物与非共价键药物的区别以及既往的重磅级共价键药物与靶标的结合特点,分类综述靶向共价键药物的理性设计及与靶标的结合反应。     

药物靶标蛋白在蛋白网络中的分布

药物靶标发现是目前生物学研究领域的热点和难点问题。从已有药物靶标中寻找规律可以为新靶标的发现总结规律,提供依据。随着功能基因组学的发展,这种组学数据的积累为这一问题的研究提供了契机。本文研究了已有靶标在蛋白网络中的分布,并分析了它们的蛋白功能域组成情况。结果显示靶标基因倾向位于网络的核心区域,并且集中在一些特定蛋白家族中。这些规律的总结将对药物研发过程中药物靶点的选择提供一定的帮助。     

药物设计与同步辐射

当代药物设计是通过阐明药物与靶标相互作用的机理,对药物先导化合物进行改造和优化。利用晶体X射线衍射的方法获得药物与靶标复合物的结构,为药物设计提供最直接有力的依据。同步辐射凭借其高强度、低发散性、波长可调谐性等得天独厚的优势,实现了对药物与靶标复合物结构的高通量测定,大大提高了基于结构的药物设计效率。     

化合物药物-靶标蛋白互作关联预测算法进展分析

药物的使用极大地提高了人类的生存质量。药物的有效性是药物发现研究中的关键环节。药物的有效性通过识别药物与其作用的靶标蛋白来判断。然而,通过高通量筛选的实验方法分析确定化合物药物-靶标蛋白互作关联是一个十分昂贵、耗时且富有挑战性的任务。基于计算方法的化合物药物-靶标蛋白互作关联预测研究具有效率高、成本低的特点,越来越受到人们的重视。相比实验验证方法,化合物药物-靶标蛋白互作关联的计算方法可为药物发现研究后续的生物药学实验提供更为准确的潜在化合物药物-靶标蛋白候选对,达到减少生物实验的时间和成本的目的。本文回顾了近20年来基于计算方法的化合物药物-靶标蛋白互作关联预测算法所涉及的生物医学特征数据、预测方法和技术,并分析研究过程中所面临的生物医学特征数据高维稀疏,以及多源生物医学数据融合程度不高等问题,为进一步研究提供有价值的参考。     

A Unique Protease Cleavage Site Predicted in the Spike Protein of the Novel Pneumonia Coronavirus (2019-nCoV) Potentially Related to Viral Transmissibility

正Dear Editor,In December 2019, a novel human coronavirus caused an epidemic of severe pneumonia(Coronavirus Disease 2019,COVID-19) in Wuhan, Hubei, China(Wu et al. 2020; Zhu et al. 2020). So far, this virus has spread to all areas of China and even to other countries. The epidemic has caused 67,102 confirmed infections with 1526 fatal cases     

Curcuminoids as inhibitors of thioredoxin reductase: A receptor based pharmacophore study with distance mapping of the active site

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzyme responsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to compare the potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results show that active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded by distance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 of demethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at least one methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites of the TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probable potent antiproliferative synthetic drugs.     

Comparative morphology of the carpel in the Liliaceae: Hewardieae, Petrosavieae, and Tricyrteae

The young pistils in the melanthioid tribes, Hewardieae, Petrosavieae and Tricyrteae, are uniformly tricarpellate and syncarpous. They lack raphide idioblasts. All are multiovulate, with bitegmic ovules. The Petrosavieae are marked by the presence of septal glands and incomplete syncarpy. Tepals and stamens adhere to the ovary in the Hewardieae and the Petrosavieae but not in the Tricyrteae. Two vascular bundles occur in the stamens of the Hewartlieae and Tricyrtis latifolia. Ventral bundles in the upper part of the ovary of the Hewardieae are continuous with compound septal bundles and placental bundles in the lower part. Putative ventral bundles occur in the alternate position in the Tricyrteae and putative placental bundles in the opposite. position in the Petrosavieae. The dichtomously branched stigma in each carpel of the Tricyrteae is supplied by a bifurcated dorsal bundle.     

Enterovirus 71 3C proteolytically processes the histone H3 N-terminal tail during infection

Highlights
1. The N-terminal tail of histone H3 is specifically cleaved during EV71 infection.
2. Viral protease 3C is identified as a protease responsible for proteolytically processing the N-terminal H3 tail.
3. Our finding reveals a new epigenetic regulatory mechanism for Enterovirus 71 in virus-host interactions.     

Detection of EBV and HHV6 in the Brain Tissue of Patients with Rasmussen’s Encephalitis

Rasmussen’s encephalitis (RE) is a rare pediatric neurological disorder, and the exact etiology is not clear. Viral infection may be involved in the pathogenesis of RE, but conflicting results have reported. In this study, we evaluated the expression of both Epstein-Barr virus (EBV) and human herpes virus (HHV) 6 antigens in brain sections from 30 patients with RE and 16 control individuals by immunohistochemistry. In the RE group, EBV and HHV6 antigens were detected in 56.7% (17/30) and 50% (15/30) of individuals, respectively. In contrast, no detectable EBV and HHV6 antigen expression was found in brain tissues of the control group. The co-expression of EBV and HHV6 was detected in 20.0% (6/30) of individuals. In particular, a 4-year-old boy had a typical clinical course, including a medical history of viral encephalitis, intractable epilepsy, and hemispheric atrophy. The co-expression of EBV and HHV6 was detected in neurons and astrocytes in the brain tissue, accompanied by a high frequency of CD8⁺ T cells. Our results suggest that EBV and HHV6 infection and the activation of CD8⁺ T cells are involved in the pathogenesis of RE.     

Perinatal Vertical Transmission of Chikungunya Virus in Ruili,a Town on the Border between China and Myanmar

正Dear Editor,Chikungunya virus (CHIKV), an arbovirus in the family of Togaviridae, genus Alphavirus, is transmitted by the A.aegyptii or A. albopictus mosquito, and causes disease in humans characterized by fever, rash, and arthralgia (Silva and Dermody 2017; Suhrbier 2019). It was first reported in 1953 in Tanzania, and caused only a few outbreaks and sporadic cases in Africa and Asia in last century. However, in the epidemic in 2004, CHIKV acquired mutations that conferred enhanced transmission by the A. albopictus mosquito(Schuffenecker et al. 2006). Since then, it has successively caused outbreaks in Africa, the Indian Ocean, South East Asia, the South America, and Europe (Zeller et al. 2016).     

Development of a Novel Reverse Transcription Loop-Mediated Isothermal Amplification Method for Rapid Detection of SARS-CoV-2

In conclusion, the novel visual RT-LAMP assay is a simple, rapid, and sensitive approach for detection of SARS-CoV-2, and it is ready for application in primary care and community hospitals or health care centers, and even patients' own houses in response to the current SARS-CoV-2 epidemic because the assay does not require sophisticated equipment and skilled personnel. Furthermore, it is also ready to be used in fields for screening samples from wild animals and environments to facilitate the identification of potential intermediate hosts that mediate the cross-species transmission of SARS-CoV-2 from bats to humans.