天然药物是国内创新药研制的突破口——专访我国著名天然药物化学专家、中国工程院院士于德泉教授

近年来,随着科技的不断进步,从天然产物中寻找有效成分开发天然药物,已成为新药研发的热点.而我国拥有1万多种药用植物资源,在开发新药过程中有得天独厚的资源优势.近日,本刊记者就目前我国利用天然产物研制新药的现状及研制过程中的相关问题,采访了我国著名的天然药物化学专家、中国工程院院士于德泉教授.     

开发微生物来源天然产物的新技术

微生物在药物的开发中具有十分重要的作用,主要表现在微生物的次级代谢产物具有结构多样性、活性广泛性和临床有效性,其中许多化合物或其衍生物已经成为临床治疗多种疾病的药物。开发微生物来源的天然产物包括寻找新资源和革新新技术。本文介绍微生物药物的优点和局限性,获得更多微生物资源的途径以及微生物药物研发中5种新技术的应用,并探讨了各自的局限性。     

以天然产物吴茱萸碱为先导结构的抗肿瘤药物设计策略研究进展

天然产物是发现抗肿瘤药物的重要来源,吴茱萸碱作为传统中药吴茱萸的有效成分,具有微弱的抗肿瘤活性,近年来,以其为先导结构开展的药物研究发现了多个高活性抗肿瘤候选药物,取得了较为显著的研究进展。本文综述了以吴茱萸碱为先导结构开展的抗肿瘤药物设计策略的研究进展,以期为以天然产物为先导结构的新药开发提供借鉴和参考。     

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。     

Carfilzomib:从天然产物到药物的研发历程

天然产物及其衍生物是药物的重要来源。Carfilzomib是一个以天然产物为先导通过结构优化得到的用于治疗多发性骨髓瘤的药物,其先导化合物Epoxomicin是从微生物中发现的具有抗癌活性的环氧酮肽类天然产物,能够选择性地抑制蛋白酶体,其环氧酮结构以独特的两步反应和蛋白酶体共价结合,因此克服了同类药物的脱靶缺点。以Epoxomicin为先导,通过结构优化得到活性更强、成药性性更好的Carfilzomib,作为新一代蛋白酶体抑制剂于2012年上市。     

海洋天然产物研究与新药开发

近年来海洋天然产物越来越引起科学家们的关注。在浩瀚的海洋中存在着大量超乎人们想象的化学结构新颖、生物活性多样、作用机制独特的次生代谢产物。海洋天然产物已成为发现重要先导药物的主要源泉。本文主要探讨近年来发现的重要的海洋天然活性产物以及在新药开发中所起的作用。     

香豆素衍生物及其抗结核活性

香豆素类化合物是一类极其重要的天然产物,广泛存在于自然界中.香豆素及其衍生物具有抗肿瘤、抗病毒、抗炎、抗氧化、抗菌和抗结核(TB)等多种生物活性,众多基于香豆素结构的药物在临床上广泛使用.近年来,香豆素及其衍生物在抗TB领域的研究引起了药物化学家的极大兴趣.药物化学家从天然产物中分离和设计合成了成千上万的香豆素衍生物,目前已从中筛选出了若干有潜力的化合物.特别值得一提的是,吡喃型香豆素类化合物(+)-Calanolide A不仅是抗HIV热点先导物,而且对药敏性和耐药性结核分枝杆菌(MTB)均显示出良好的体内外活性,无疑可用于治疗MTB/HIV双重感染患者.本文将着重探讨香豆素衍生物抗TB的构-效关系,为寻找疗效更高、毒副作用更小的香豆素类抗TB新药提供理论依据.     

诱变合成法用于药物发现

[英]?WeissmanKJ∥Trends Biotechnol.-2007,25(4).-139～141许多药用天然产物结构独特,难以用全合成或者半合成的方法制备。早期的合成方法为基于前体的生物合成,即将合成的化合物经过细菌或真菌的生物转化生成天然药物。但是与内源性前体存在竞争,终产物产率较低。如果将此细菌或真菌的合成,变成基于细胞的合成,并且经过遗传改造使得合成通路变得特异,则成为诱变合成法。诱变合成法联合了化学和遗传学原理,将化学合成和分子生物学结合起来,可用于制备具有药用价值的天然产物及其衍生物。最早于40年前即应用诱变合成法的原理,从新霉素的…     

天然药物开发应用前景

天然药物对疑难症、慢性病及老年病有特殊疗效,毒副作用小,深受患者欢迎.天然药物包含动植物药物、生物技术药物及化学合成的天然药物等.从天然产物中寻找和开发新药已成为世界医药界研究热点.我国也正加速天然药物研制与开发,以迎接医药经济全球化的挑战.     

收获天然产物的硕果

对于高通量筛选 ,天然产物优于合成化合物的关键是其结构的多样性。德国拜耳公司的Ｈｅｎｋｅｌ及其同事在比较天然产物和合成化合物数据库后 ,发现天然产物中有合成化合物库中没有的化学骨架占 4 0 %。因此 ,如果筛选中有多种天然产物参与 ,寻找新先导化合物就更可能获得成功。因为实际和可能存在的困难 ,药厂对高通量筛选中应用更多的天然产物还存有疑虑。此种限制包括 :天然产物的化学复杂性 ;筛选提取物中混合成分的困难 ;天然产物化学的耗时性 ;筛选天然产物带来的大量假阳性 ;提取物不同组分间可能发生的协同作用 ;由于植物代谢的季节…     

Natural Products in Drug Discovery and Development. 27-28 June 2005, London, UK

The meeting covered many aspects of the use of natural products in drug discovery and development. The historical and current contributions of natural products to the main classes of medicines, technical improvements to the supply of marine microbial products by fermentation and molecular biology and the value of natural chemical diversity for providing patentable, drug-like lead molecules were among the topics discussed. Several compounds in current clinical trials were described; these included several anticancer compounds and two compounds in development by Phytopharm plc, PYM-50028 (Cogane) and PYM-50018 (Myogane), for the treatment of neurodegenerative disease.     

Technology for improving the bioavailability of small molecules extracted from traditional Chinese medicines

Evidence that small molecules extracted from traditional Chinese medicines (TCMs) have beneficial effects on health is increasingly being reported in the scientific literature and these compounds are now widely recognized as potential therapeutic drugs. There have been several detailed studies of the absorption, distribution, metabolism and excretion of these compounds in rats and humans. However, some active components have low bioavailability owing to their unsuitable physicochemical and biopharmaceutical characteristics, resulting in differences in vivo. The main problem in using natural products as a source of pharmaceutical lead compounds is the need to improve the bioavailability of these compounds. This review presents and discusses the current methods used for improvement and their impact on the bioavailability of some new pharmaceutical lead compounds from TCMs.     

Recent advances in screening active components from natural products based on bioaffinity techniques

Natural products have provided numerous lead compounds for drug discovery. However, the traditional analytical methods cannot detect most of these active components, especially at their usual low concentrations, from complex natural products. Herein, we reviewed the recent technological advances (2015–2019) related to the separation and screening bioactive components from natural resources, especially the emerging screening methods based on the bioaffinity techniques, including biological chromatography, affinity electrophoresis, affinity mass spectroscopy, and the latest magnetic and optical methods. These screening methods are uniquely advanced compared to other traditional methods, and they can fish out the active components from complex natural products because of the affinity between target and components, without tedious separation works. Therefore, these new tools can reduce the time and cost of the drug discovery process and accelerate the development of more effective and better-targeted therapeutic agents.     

Production of paclitaxel and the related taxanes by cell suspension cultures of Taxus species

Medicinal plants are the most promising source for the development of drugs, and many types of active ingredients from the plant resources have been studied in order to clarify the relationship between the chemical structure and the activity. However, it is not easy to develop drugs from those active compounds, and in many cases, the supply of active compounds can have some problems: 1) limited quantity of active compounds in plant; 2) low plant growth rate; 3) the limited localization of active ingredients in the specific organs; and 4) from the perspective of the conservation of natural resources. Therefore, the stable supply of the compounds commercially is very difficult and contains risk hedge. Plant cell culture is an attractive technology to solve these problems by securing the stable supply of the active compounds without damage to the natural plant resources. Recently, an efficient production process of anticancer drug paclitaxel by Taxus cell suspension cultures was constructed. The established Taxus cell lines produced paclitaxel and related taxanes by specific external stimuli, such as methyl jasmonate. The time-course analysis revealed that there are two regulatory steps existing in the paclitaxel biosynthesis: the taxane-ring formation step that is up-regulated by MeJA, and the acylation step at the C-13 position. By applying the data from the two-stage culture and the high-density culture, a large-scale culture process was developed with a stable paclitaxel production in the range of 140-295 mg L(-1), reaching 295 mg L(-1) at maximum.     

Natural peroxy anticancer agents

Present review describes research on novel natural anticancer agents isolated from terrestrial and marine sources. More than 120 cytotoxic anticancer compounds have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to Natural Cancer Institute for further in vivo evaluation. Intensive searches for new classes of pharmacologically potent agents produced by terrestrial and marine organisms have resulted in the discovery of dozens of compounds possessing high cytotoxic activities. However, only a limited number of them have been tested in pre-clinical and clinical trials. One of the reasons is a limited supply of the active ingredients from the natural sources. However, the pre-clinical and clinical development of many terrestrial and/or marine-derived natural products into pharmaceuticals is often hampered by a limited supply from the natural source. Total synthesis is of vital importance in these situations, allowing for the production of useful quantities of the target compound for further biological evaluation. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of terrestrial and marine peroxides as an important source of leads for drug discovery.     

Biosynthetic engineering of natural products for lead optimization and development

It is now possible to rapidly and rationally modify, at a genetic level, the machinery responsible for natural product biosynthesis. This provides the opportunity to design new structures and to optimize natural product lead compounds in a way that would be extremely difficult through synthetic chemistry means alone. The technology can also be used to overcome limitations of compound supply, which might otherwise preclude natural products from progressing into clinical trials. Described herein are some recent examples which highlight how biosynthetic engineering has been applied to drug discovery and development, and which attempt, in particular, to demonstrate how the technology functions most effectively when combined with synthetic organic and medicinal chemistry.     

Chemistry and biology of new marine alkaloids from the indole and annelated indole series

Chemistry and biology of marine natural products from the indole and annelated indole series have become an attractive research field for development of new pharmacological lead substances. In the past years some of the isolated natural organic compounds were synthesized by chemists and evaluated with great enthusiasm to find new lead natural compounds against different diseases. In this review the latest results for new compounds including isolation, biological evaluation, synthetic pathways and some retrosynthetic analyses are summarized.     

Virtual screening and molecular dynamics simulation analysis of Forsythoside A as a plant-derived inhibitor of SARS-CoV-2 3CLpro

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a more severe strain of coronavirus (CoV) that was first emerged in China in 2019. Available antiviral drugs could be repurposed and natural compounds with antiviral activity could be safer and cheaper source of medicine for SARS-CoV-2. 78 natural antiviral compounds database was identified from literature and virtual screening technique was applied to identify potential 3-chymotrypsin-like protease (3CLpro) inhibitors. Molecular docking studies were conducted to analyze the main protease (3CLpro) and inhibitors interactions with key residues of active site of target protein (PDB ID: 6LU7), active site constitute the part of active domain I and II of 3CLpro. 10 compounds with highest dock score were subjected to calculate ADMET parameters to figure out drug-likeness. Molecular dynamic (MD) simulation of the selected lead was performed by Amber simulation package to understand the conformational changes in docked complex. MD simulations analysis (RMSD, RMSF, Rg, BF, HBs, and SASA plots) of lead bounded with 3CLpro, hence revealed the important structural turns and twists during MD simulations from 0 to 100 ns. MM-PBSA/GBSA methods has also been applied for the estimation binding free energy (BFE) of the selected lead-complex. The present study has identified lead compound “Forsythoside A” an active extract of Forsythia suspense as SARS-CoV-2 3CLpro inhibitor that can block the viral replication and translation. Structural analysis of target protein and lead compound performed in this study could contribute to the development of potential drug against SARS-CoV-2 infection.     

一株南沙群岛柳珊瑚来源真菌 Aspergillus terreus 中化合物及 mPTPB 酶抑制活性研究

目的 从1株南沙群岛柳珊瑚来源真菌 Aspergillus terreus (NS02-09)中分离鉴定海洋天然产物,对所得化合物进行结核分枝杆菌酪氨酸磷酸激酶 (mPTPB) 抑制活性评价。方法 运用多种色谱手段分离纯化化合物,利用NMR、CD等现代波谱分析方法,对化合物进行结构鉴定、,通过衍生物制备获得两个乙酰化衍生物(2a和2b);并对化合物2及其衍生物2a和2b进行mPTPB酶抑制活性测试。结果 鉴定了1个土曲霉酮(1)和1个丁烯酸内酯 (2) 的结构; 2具有较强的mPTPB酶抑制活性,而其乙酰化产物(2a和2b)的mPTPB 酶抑制活性显著降低。运用Sybyl X 1.3 软件,对2与mPTPB酶的模拟对接计算发现,丁烯酸内酯环及环上的羟基是化合物2发挥酶抑制活性的重要作用基团。结论 从柳珊瑚来源真菌 A. terreus (NS02-09) 中发现了具有mPTPB 酶抑制活性的丁烯酸内酯类化合物,并对其作用机制进行了计算研究,该类化合物的相关研究对抗结核药物先导化合物发现具有借鉴作用。