我国中药来源的抗HIV天然化合物研究进展

由于迄今仍无艾滋病 (acquired immunodeficiency syndrome, AIDS) 疫苗问世, 抗人类免疫缺陷病毒 (human immunodeficiency virus, HIV) 药物仍然是艾滋病治疗的主要手段。传统中药和药用植物来源的天然化合物具有结构多样性、毒性较低、来源广泛等特点, 因而在防治艾滋病方面有着独特的优势和巨大的潜力。研究者已经对天然化合物抗HIV作用进行了大量研究, 并取得了可喜的成绩, 发现了一些生物碱、香豆素、木脂素、黄酮类、萜类、鞣质类、多糖类、蛋白质和多肽类等天然化合物具有抗HIV的活性。然而, 多数研究都是在体外试验完成的, 大多数天然化合物体外抗HIV活性偏低, 而且抗HIV的靶点仍不十分清楚。本文结合笔者实验室研究工作, 重点介绍近年来我国传统中药来源的抗HIV活性较强的天然化合物研究进展。     

中药和天然药物抗HIV研究进展

由人类免疫缺陷病毒(human immunodeficiency virus, HIV)引起的艾滋病已成为全球性重大公共卫生问题,影响了全球约7000万人。目前的高效抗逆转录病毒疗法(highly active anti-retroviral therapy, HAART)虽可抑制HIV,但不能完全根除病毒感染。临床研究显示中药及其复方能有效降低HIV病毒载量,减轻艾滋病病情,提高患者生活质量。从中药和天然药物中寻找优势骨架类型的活性分子已成为抗艾滋病药物研究的重要策略。本文围绕临床应用的抗HIV单品药物、临床应用的抗HIV中药复方、中药和天然药物中的抗HIV活性成分和作用机制等方面进行综述,为发现新型治疗艾滋病的药物提供有价值的参考。     

抗HIV药物研究进展及发展趋势

本文分类总结了近年来抗HIV药物的研究进展以及以后的发展趋势,着重介绍了抗HIV的新的作用靶点和天然活性产物在抗HIV方面的应用。     

艾滋病中西医治疗

1 抗人类免疫缺陷病毒(HIV)的药物1.1 核苷类和非核苷类经研究得知,HIV对靶细胞的感染全过程可分为几个阶段,HIV感染靶细胞的每个阶段都可以成为抗HlV药物作用的靶子.经获准在临床上使用最广的是核苷类药     

新的抗艾滋病药物——趋化因子受体拮抗剂的研究进展

目前,在艾滋病研究领域中对趋化因子及其受体的研究受到极大关注。而趋化因子受体可作为HIV-1进入T细胞的协同受体这一重大发现,为人类寻找新的抗HIV/AIDS药物提供了新的思路,即以趋化因子受体为靶点,筛选能够与该受体结合并随即阻碍HIV-1进入细胞的药物。目前针对HIV/AIDS治疗而开发的几类趋化因子受体拮抗剂都还处于临床试验阶段。本文将对趋化因子受体及趋化因子受体结抗剂的研究进展进行扼要综述。     

白桦酸及其衍生物的研究进展

对白桦酸衍生物的构效关系及其中的YK-FH312、RPR103611和IC9564等的作用机制及活性进行述评。天然产物白桦酸是有抗HIV和抗肿瘤活性，且具有新型结构和新型作用机制的化合物，其天然来源广泛，半合成方法成熟，是寻找抗HIV和抗肿瘤药物的优秀的先导物。通过对白桦酸的结构修饰，大量白桦酸衍生物已被合成。     

抗分枝杆菌植物天然产物研究进展

由分枝杆菌引起的感染是人类健康的巨大威胁。目前,多种结核分枝杆菌和非结核分枝杆菌对临床抗分枝杆菌药物具有较高的耐药性。中药治疗分枝杆菌感染具有悠久历史。例如,中药材狼毒已应用于抗结核分枝杆菌的治疗。非中药来源的植物中,也蕴含丰富的抗分枝杆菌成分。这些植物来源的天然产物具有较好的结构多样性,是开发抗分枝杆菌药物的潜在来源。本文综述了近年来在中药和其他非中药来源植物中发现的,具有良好抗分枝杆菌活性的化合物或提取物,并介绍了它们的作用机制。这些活性植物天然产物为新抗分枝杆菌药物的发现提供了化合物库。同时,这些植物天然产物结构与现有抗分枝杆菌药物具有显著的差别,研究其作用机制,也可发现新的抗分枝杆菌靶标。     

天然产物中抗HIV生物碱类化合物的研究进展

近年来,从天然产物中寻找高效低毒的先导化合物已成筛选抗HIV药物的重要研究方向。生物碱类化合物作为一类重要的天然产物,数量众多,结构类型复杂,其中有多种抑制和阻断HIV感染的有效成分,通过实验室研究工作和临床用药观察,有望从中获得抗HIV的有效药物。以生物碱类化合物的化学结构为基础,将生物碱类化合物分为异喹啉类、喹啉类、大环类、哌啶类、莨菪烷类、吲哚类、咔唑类、海洋多环胍类、萜类、manzamine型生物碱等10类,对其抗HIV活性进行综述。     

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。     

抗艾滋病药物设计新策略:多靶点及多价态结合配体

HIV是艾滋病(AIDS)的主要病原体,由于目前临床药物严重的耐药性问题以及长期应用的毒副作用,研发高效抗耐药的抗艾滋病药物及全新疗法是当前药物化学领域的研究热点。近年来,多靶点和多价态结合药物越来越受到研究者的关注,并且成为合理设计抗艾滋病药物的新途径。本文结合具体实例综述了合理设计多靶点及多价态抗艾滋病药物的新进展,并对目前存在的问题和研究趋势进行了总结和展望,为发现新一代抗HIV药物提供重要信息。     

Anthraquinones: analytical techniques as a novel tool to investigate on the triggering of biological targets

Approximately, 63% of marketed drugs derive from natural products or their semi synthetic derivatives. Compounds from living organisms often exert a biological activity, triggering several targets, which may be useful for the improvement of novel pharmaceuticals. These natural products can be extracted from plants, marine organisms, or microorganism fermentation broths. In the vast array of bioactive secondary metabolites known up to now, anthraquinones are among the most investigated natural products, in particular for what concerns their mechanism of action. This review focuses on the analytical aspects of anthraquinones, from their separation to recent and new high-throughputs techniques for the simultaneous determination of these analytes in biological matrices that can greatly contribute to sharply depict the targets of these secondary metabolites as well as on an updated survey of their biological activities.     

Sesquiterpenes: natural products that decrease cancer growth

Despite recent advances in our understanding of the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. One of the oldest and most effective strategies for developing new chemotherapeutics is the isolation and evaluation of chemicals of natural origin. The importance of natural products for drug discovery has been impressive: One has to only look at the number of clinically active drugs that are used in cancer therapy to see how many are either natural products or are based on natural products. It is also apparent that materials from natural sources are excellent probes (indicators) for cellular targets that, when modulated, may have a deleterious effect upon the survival or proliferation of tumor cells. And the search goes on. Sesquiterpenes are a class of naturally occurring molecules that have demonstrated therapeutic potential in decreasing the progression of cancer. These molecules are 15-carbon isoprenoid compounds that are typically found in plants and marine life. Although this class of compounds has frequently provided encouraging leads for chemotherapeutics, they have not been evaluated as potential anticancer agents. In this review, we provide a current overview of sesquiterpenoids that have potential as anticancer agents.     

Applied metabolomics in drug discovery

ABSTRACT

Introduction: The metabolic profile is a direct signature of phenotype and biochemical activity following any perturbation. Metabolites are small molecules present in a biological system including natural products as well as drugs and their metabolism by-products depending on the biological system studied. Metabolomics can provide activity information about possible novel drugs and drug scaffolds, indicate interesting targets for drug development and suggest binding partners of compounds. Furthermore, metabolomics can be used for the discovery of novel natural products and in drug development. Metabolomics can enhance the discovery and testing of new drugs and provide insight into the on- and off-target effects of drugs.

Areas covered: This review focuses primarily on the application of metabolomics in the discovery of active drugs from natural products and the analysis of chemical libraries and the computational analysis of metabolic networks.

Expert opinion: Metabolomics methodology, both experimental and analytical is fast developing. At the same time, databases of compounds are ever growing with the inclusion of more molecular and spectral information. An increasing number of systems are being represented by very detailed metabolic network models. Combining these experimental and computational tools with high throughput drug testing and drug discovery techniques can provide new promising compounds and leads.     

Natural Products as a Resource for New Drugs

Natural products have served as a major source of drugs for centuries, and about half of the pharmaceuticals in use today are derived from natural products. The aim of this review is to provide an overview of the continuing central role of natural products in the discovery and development of new pharmaceuticals. In this context, selected examples of important natural product-derived drugs are cited, focusing on some of the most recent introductions to the clinical setting, and a brief overview of some of the important recent developments and remaining challenges in the process of discovering and developing bioactive natural products is provided. Interest in natural products research is strong and can be attributed to several factors, including unmet therapeutic needs, the remarkable diversity of both chemical structures and biological activities of naturally occurring secondary metabolites, the utility of bioactive natural products as biochemical and molecular probes, the development of novel and sensitive techniques to detect biologically active natural products, improved techniques to isolate, purify, and structurally characterize these active constituents, and advances in solving the demand for supply of complex natural products. Opportunities for multidisciplinary research that joins the forces of natural products chemistry, molecular and cellular biology, synthetic and analytical chemistry, biochemistry, and pharmacology to exploit the vast diversity of chemical structures and biological activities of natural products are discussed.     

多靶点抗肿瘤天然产物研究进展

天然产物及其衍生物是抗肿瘤药物的重要组成部分.目前在临床上应用的天然产物来源的抗肿瘤药物以传统细胞毒类药物或靶向某一特定靶点的分子靶向药物为主,其应用受限于药物相关不良反应和肿瘤耐药.近年的研究表明,抗肿瘤活性天然产物往往能够靶向肿瘤细胞的多个靶点,影响肿瘤发生发展中的多个过程.由于肿瘤是一种多因素诱发的系统性疾病,多...     

A review on plant-derived natural products and their analogs with anti-tumor activity

Traditional medicines, including Chinese herbal formulations, can serve as the source of potential new drugs, and initial research focuses on the isolation of bioactive lead compound(s). The development of novel plant-derived natural products and their analogs for anticancer activity details efforts to synthesize new derivatives based on bioactivity- and mechanism of action-directed isolation and characterization coupled with rational drug design - based modification. Also, the anticancer activity of certain natural products and their analogs can be enhanced by synthesizing new derivatives based on active pharmacophore models; drug resistance and solubility and metabolic limitations can be overcome by appropriate molecular modifications; and new biological properties or mechanisms of action can be added by combining other functional groups or molecules. Preclinical screening for in vitro human cell line panels and selected in vivo xenograft testing then identifies the most promising drug development targets.     

海洋药物研究开发进展

新颖结构和重要生物活性天然产物的发现是创新药物开发的关键要素。海洋生物资源以其多样性、复杂性、特殊性成为新药研发中先导化合物的重要来源,截止目前基于海洋天然产物或其衍生物开发而成功上市的药物有16种,进入III期、II期、I期临床研究的活性物质分别有8、14、7种,而折戟于临床阶段的有4种;本文对其生物来源、作用机理、临床研究进展作了简要概述,期待海洋药物学科能更快、更好地发展,产生更多新药,为人类重大疾病的治疗做出重大贡献。     

Sleeping sickness pathogen (Trypanosoma brucei) and natural products: therapeutic targets and screening systems

Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) which is fatal if left untreated. This disease occurs in 36 African countries, south of the Sahara, where 60 million people are at risk of acquiring infection. The current chemotherapy relies on only four drugs, three of which were developed more than 60 years ago. These drugs have many limitations, ranging from oral inabsorption, acute toxicities, short duration of action and the emergence of trypanosomal resistance. Despite decades of use of most of the current trypanocides, little is known about their mode of action. That being said, African trypanosomes continue to be among the most extensively studied parasitic protists to date. Many of their intriguing biological features have been well documented and can be viewed as attractive targets for antitrypanosomal chemotherapy. A considerable number of natural products with diverse molecular structures have revealed antiparasitic potency in the laboratory and represent interesting lead compounds for the development of new and urgently needed antiparasitics. The major validated drug targets in T. brucei are discussed with particular emphasis on those known to be attacked by natural compounds.     

Antiretroviral drug development for HIV: challenges for the future

The scarcity of new innovative drugs in the development pipeline for combating HIV replication may signal a change in direction for HIV researchers and drug developers. The model of introducing drugs with incremental improvements within existing drug classes is no longer commercially viable. While an argument can be made that drugs aimed at novel targets may have a greater impact, the list of such targets is limited and the scientific challenge of intervening at another stage in the HIV replication cycle is high. It is difficult to envision a realistic risk/reward scenario that will ensure continued investment in the discovery of novel HIV drugs that simply block replication and suppress plasma viral load. Recently, it has been suggested that the scientific community should move research in a new direction, with the goal of attacking the reservoirs of latent HIV that persist despite treatment with current drugs to achieve a functional cure, if not a sterilizing cure. This process will have to be a long-term commitment, primarily funded by the NIH, with some involvement by the pharmaceutical and biotechnology industries. While most individuals infected with HIV can achieve viral suppression with the current approved therapies, treatment is lifelong, side effects are significant and resistance will eventually render more of these drugs less effective. New and innovative approaches must be developed to prevent viral infection and further improve the quality of life for those individuals who are already infected.     

植物红豆杉的抗癌药用价值研究简

目的了解抗癌成分紫杉醇对各种癌症的治疗效果。方法从化学成分紫杉醇的提取及抗癌机理的研究来阐述红豆杉的抗癌作用。结果红豆杉成分紫杉醇经研究证实疗效显著、不良反应小,是难得的天然抗癌药物。结论由于生长缓慢,人为破坏严重,资源严重短缺,合理利用生物资源治疗肿瘤是人类关注的抗癌药研究发展方向之一。