Biological screening of natural products and drug innovation in China

Natural products have been applied to human healthcare for thousands of years. Drug discovery in ancient times was largely by chance and based on clinical practices. As understanding of therapeutic benefits deepens and demands for natural products increase, previously serendipitous discoveries evolve into active searches for new medicines. Many drugs presently prescribed by physicians are either directly isolated from plants or are artificially modified versions of natural products. Scientists are looking for lead compounds with specific structures and pharmacological effects often from natural sources. Experiences and successes of Chinese scientists in this specialized area have resulted in a number of widely used drugs. The tremendous progress made in life sciences has not only revealed many pathological processes of diseases, but also led to the establishment of various molecular and cellular bioassays in conjunction with high-throughput technologies. This is advantageous and permits certain natural compounds that are difficult to isolate and purify, and compounds that are difficult to synthesize, to be assayed. The transition from traditional to empirical and to molecular screening will certainly increase the probability of discovering new leads and drug candidates from natural products.     

Ecopharmacognosy and the responsibilities of natural product research to sustainability

The recently developed term “ecopharmacognosy” is defined as the study of sustainable, biologically active, natural resources. As a philosophical approach, it provides a conceptual framework for developing new strategies and new scientific perspectives which may improve future global food and health care product accessibility and assure beneficial outcomes. In this brief article some facets of how the precepts of ecopharmacognosy may apply in developing new medicinal products may be developed, based on sustainability and the use of integrated technologies.Although from a medicinal agent perspective, plants remain a primary source of global health care, these resources are not being pursued by major pharmaceutical companies as sources of new agents, and essentially all tropical diseases, as well as most microbially based diseases, remain outside the scope of their drug discovery programs. Countries and regions therefore must address their own drug discovery needs for “local” and some global diseases. In addition, the cost of drug importation is so high that development of local resources, i.e. traditional medicines, may be the only rational alternative approach. At the same time, network pharmacology is exploring the many diverse effects of both individual and complex natural products at the gene level, and this is offering new opportunities to rethink and restructure the core, long-standing, Western, magic bullet philosophy to drug discovery. Other ecopharmacognosy changes underway include the computer-aided design of natural product derivatives, based on molecular docking, which is providing targetable enzyme substrates, and remote sensing technologies which can assess natural materials non-invasively for critical constituents as a part of rethinking quality control strategies in the field. Furthermore, there are the hyphenated chromatographic and spectroscopic procedures to quantitatively analyze single and multicomponent plant mixtures for bioactive markers to enhance quality control and, thereby, patient care. The relationship of these evolving approaches will serve as practical examples to the philosophies of ecopharmacognosy. In summary, with respect to health care, ecopharmacognosy poses the long-term practical question for drugs, “How Green is Your Medicine?”     

Plant natural products: Back to the future or into extinction?

Natural product substances have historically served as the most significant source of new leads for pharmaceutical development. However, with the advent of robotics, bioinformatics, high throughput screening (HTS), molecular biology-biotechnology, combinatorial chemistry, in silico (molecular modeling) and other methodologies, the pharmaceutical industry has largely moved away from plant derived natural products as a source for leads and prospective drug candidates. Can, or will, natural products ever recapture the preeminent position they once held as a foundation for drug discovery and development? The challenges associated with development of natural products as pharmaceuticals are illustrated by the Taxol^® story. Several misconceptions, which constrain utilization of plant natural products, for discovery and development of pharmaceuticals, are addressed to return natural products to the forefront.     

Combination therapy: A new strategy to manage diabetes and its complications

Diabetes mellitus is the most common metabolic disorder. The major cause of mortality and morbidity here is due to the complications caused by increased glucose concentrations. All the available commercial antidiabetic drugs are associated with side effects. The combination therapy could be a new and highly effective therapeutic strategy to manage hyperglycemia. Combination of commercial drugs with phytochemicals may reduce the side effects caused by these synthetic drugs. Herbal products have been thought to be inherently safe, because of their natural origin and traditional use rather than based on systemic studies. New formulation and cocrystallisation strategies need to be adopted to match the bioavailability of the drug and the phytochemical. This review describes in detail, the observed synergy and mechanism of action between phytochemicals and synthetic drugs in effectively combating. The mode of action of combination differs significantly than that of the drugs alone; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries.     

植物天然产物微生物重组合成研究进展

植物天然产物是小分子药物、营养品、化妆品、香精香料等的主要来源之一,在国民经济中发挥重要的作用。目前植物天然产物主要依赖于植物提取,这种生产方式占用耕地、生长周期长,而且植物活性成分往往含量低、生产成本高。通过解析植物天然产物生物合成途径,在微生物细胞中重构,创建细胞工厂,实现利用可再生原料发酵合成,为植物天然产物的供给提供了新的路线。本文重点介绍了中国科学院天津工业生物技术研究所在萜类、黄酮类、苯丙素类等重要类型植物天然产物微生物重组合成方面的研究进展,简要探讨了当前研究面临的挑战及未来前景。     

Potential of plant cells in culture for cosmetic application

Plants and plant derived ingredients are common and of major importance in the fields of pharmacy, food and cosmetics. The cosmetic industry is a fast moving market. Products have short life-cycles and the industry has to come up with innovative products constantly. Most cosmetic products and their applications are defined by active ingredients. These active ingredients may derive from either synthetic sources or from plant sources. Beside this, no other origin like human or animal are accepted or allowed in cosmetics nor are genetically modified plant sources. The whole cosmetic research and development society is therefore desperately seeking for new innovative plant ingredients for cosmetic application. Unfortunately, new plant derived ingredients are limited because several plants of cosmetic interest are not to be used due to following facts: the plants contain toxic metabolites, the plants grow too slow and a seasonal harvesting is not possible, the concentration of plant constituents differ from harvest to harvest or the plant is endangered and not allowed to harvest. With the plant cell culture technology we bring complete new aspects in the development of novel cosmetic plant derived actives. Due to all these findings, we decided to risk the step into plant cell culture derived cosmetic active ingredient production. This article describes the successful establishment of an apple suspension culture producing a high yield of biomass, cultured in disposable, middle-scale bioreactors. The use of a bioactive extract out of these cells for cosmetic application and the efficacy of this extract on mammalian stem cells is also outlined in this article. To obtain a suitable cosmetic product we used the high pressure homogenization technique to decompose the plant cells and release all the beneficial constituents while encapsulating these components at the same time in liquid Nanoparticles. With the plant cell culture technology we bring complete new aspects in the development of novel cosmetic plants derived actives.     

Synergy research: Approaching a new generation of phytopharmaceuticals

The longstanding, successful use of herbal drug combinations in traditional medicine makes it necessary to find a rationale for the pharmacological and therapeutic superiority of many of them in comparison to isolated single constituents. This review describes many examples of how modern molecular–biological methods (including new genomic technologies) can enable us to understand the various synergistic mechanisms underlying these effects. Synergistic effects can be produced if the constituents of an extract affect different targets or interact with one another in order to improve the solubility and thereby enhance the bioavailability of one or several substances of an extract. A special synergy effect can occur when antibiotics are combined with an agent that antagonizes bacterial resistance mechanisms. The verification of real synergy effects can be achieved through detailed pharmacological investigations and by means of controlled clinical studies performed in comparison with synthetic reference drugs. All the new ongoing projects aim at the development of a new generation of phytopharmaceuticals which can be used alone or in combination with synthetic drugs or antibiotics. This new generation of phytopharmaceuticals could lend phytotherapy a new legitimacy and enable their use to treat diseases which have hitherto been treated using synthetic drugs alone.     

New perspectives for synergy research with the “omic”-technologies

Synergistic effects, understood as true overadditive effects, are often observed in experimental and clinical studies using phytopharmaceuticals. The introduction of the “omic”-technologies is now opening new perspectives in rationalizing these effects and making use of them in the development of a new generation of phytopharmaceuticals. This review describes possible mechanism of synergistic actions of herbal drugs by mono- and multitargeting and by the activation of signal cascades. It examins the possibilities of the standardization of single and multi component plant extracts and the prediction and assessment of the toxicity and safety of plant extracts with the support of the “omic”-technologies. It further discusses the use of phytopharmaceuticals in the context of an “individualized medicine”. It makes proposals how to use the “omic”-technologies to rationalize and develop combination therapies of phytopharmaceuticals and synthetic drugs to minimize adverse reactions (ARs) or improve the therapeutic efficacy. Examples of clinical studies are given which explore already the potential of such co-medications. Modern medical therapy has acknowledged for quite some time the usefulness of combination therapies in the treatment of multifactorial diseases like cancer, cardiovascular or rheumatic diseases. The term “synergy” is rarely used in this context, the combinatory mechanisms of actions seldom completely understood and the potentially occurring adverse reactions feared. A systematic exploitation of synergy effects of phytomedical interventions alone or in combination with synthetic drugs should lead in a long term perspective to the discovery and development of more rational evidence-based interventions in the prevention and therapy of multifactorial diseases and should thereby enrich modern pharmacotherapy.     

高通量植物生物反应器及其在遗传资源挖掘中的应用

生物反应器(bioreactor)是一种以表达目标产物或获得繁殖体为目的的设备系统,包括微生物、动物、植物生物反应器以及相关设备。植物生物反应器(phytobioreactor)是借鉴植物组织培养和微生物发酵原理制作的设备系统。其中,应用较广泛的是间歇浸没式植物生物反应器。与传统植物组织培养相比,该方法具备可换气、无需转接和大容量培养等特点。国内制作的BIOF系列新型植物生物反应器还可以利用串/并联方法,实现更高通量培养能力,其应用于植物种苗繁育、代谢产物的表达、耐盐等变异的定向筛选、植物生长发育的动态分析等方面均具备显著优势。现代植物生物技术在基础研究和产业方面的应用对植物生物反应器提出了新要求,新型生物反应器应用方法的持续改进和设备系统的不断完善,使其成为植物学领域的高效研究平台,并将促进植物育种和植物源化合物的发掘等方面研究效率的提高。     

New aspects of natural products in drug discovery

During the past 15 years, most large pharmaceutical companies have decreased the screening of natural products for drug discovery in favor of synthetic compound libraries. Main reasons for this include the incompatibility of natural product libraries with high-throughput screening and the marginal improvement in core technologies for natural product screening in the late 1980s and early 1990 s. Recently, the development of new technologies has revolutionized the screening of natural products. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. Examples of these new advances and technologies are described in this review.     

Natural Products in High Throughput Screening: Automated High-Quality Sample Preparation

At present, compound libraries from combinatorial chemistry are the major source for high throughput screening (HTS) programs in drug discovery. On the other hand, nature has been proven to be an outstanding source for new and innovative drugs. Secondary metabolites from plants, animals, and microorganisms show a striking structural diversity that supplements chemically synthesized compounds or libraries in drug discovery programs. Unfortunately, extracts from natural sources are usually complex mixtures of compounds, often generated in time-consuming and, for the most part, manual processes. Because quality and quantity of the provided samples play a pivotal role in the success of HTS programs, this poses serious problems. In order to make samples of natural origin competitive with synthetic compound libraries, we devised a novel, automated sample preparation procedure based on solid-phase extraction (SPE). By making use of modified Zymark (Hopkinton, MA) RapidTrace? SPE workstations, we developed an easy-to-handle and effective fractionation method that generates high-quality samples from natural origin, fulfilling the requirements for an integration in high throughput drug discovery programs.     

Exploring anti-TB leads from natural products library originated from marine microbes and medicinal plants

Multidrug-resistant tuberculosis (MDR-TB) and TB–HIV co-infection have become a great threat to global health. However, the last truly novel drug that was approved for the treatment of TB was discovered 40?years ago. The search for new effective drugs against TB has never been more intensive. Natural products derived from microbes and medicinal plants have been an important source of TB therapeutics. Recent advances have been made to accelerate the discovery rate of novel TB drugs including diversifying strategies for environmental strains, high-throughput screening (HTS) assays, and chemical diversity. This review will discuss the challenges of finding novel natural products with anti-TB activity from marine microbes and plant medicines, including biodiversity- and taxonomy-guided microbial natural products library construction, target- and cell-based HTS, and bioassay-directed isolation of anti-TB substances from traditional medicines.     

Endophytic fungi: novel sources of anticancer lead molecules

Cancer is a major killer disease all over the world and more than six million new cases are reported every year. Nature is an attractive source of new therapeutic compounds, as a tremendous chemical diversity is found in millions of species of plants, animals, and microorganisms. Plant-derived compounds have played an important role in the development of several clinically useful anti-cancer agents. These include vinblastine, vincristine, camptothecin, podophyllotoxin, and taxol. Production of a plant-based natural drug is always not up to the desired level. It is produced at a specific developmental stage or under specific environmental condition, stress, or nutrient availability; the plants may be very slow growing taking several years to attain a suitable growth phase for product accumulation and extraction. Considering the limitations associated with the productivity and vulnerability of plant species as sources of novel metabolites, microorganisms serve as the ultimate, readily renewable, and inexhaustible source of novel structures bearing pharmaceutical potential. Endophytes, the microorganisms that reside in the tissues of living plants, are relatively unstudied and offer potential sources of novel natural products for exploitation in medicine, agriculture and the pharmaceutical industry. They develop special mechanisms to penetrate inside the host tissue, residing in mutualistic association and their biotransformation abilities opens a new platform for synthesis of novel secondary metabolites. They produce metabolites to compete with the epiphytes and also with the plant pathogens to maintain a critical balance between fungal virulence and plant defense. It is therefore necessary that the relationship between the plants and endophytes during the accumulation of these secondary metabolites is studied. Insights from such research would provide alternative methods of natural product drug discovery which could be reliable, economical, and environmentally safe.     

Endophytic fungi isolated from medicinal plants: future prospects of bioactive natural products from Tabebuia/Handroanthus endophytes

Medicinal plants are a rich source of natural products used to treat many diseases; therefore, they are the basis for a new drug discovery. Plants are capable of generating different bioactive secondary metabolites, but a large amount of botanical material is often necessary to obtain small amounts of the target substance. Nowadays, many medicinal plants are becoming rather scarce. For this reason, it is important to point out the interactions between endophytic microorganisms and the host plant, because endophytes are able to produce highly diverse compounds, including those from host plants that have important biological activities. Thence, this review aims at presenting the richness in bioactive compounds of the medicinal plants from Tabebuia and Handroanthus genera, as well as important aspects about endophyte-plant interactions, with emphasis on the production of bioactive compounds by endophytic fungi, which has been isolated from various medicinal plants for such a purpose. Furthermore, bio-prospection of natural products synthesized by endophytes isolated from the aforementioned genera used in traditional medicine could be used to treat illnesses.

     

Synergism between natural products and antibiotics against infectious diseases

Antibiotics have been effective in treating infectious diseases, but resistance to these drugs has led to the emergence of new and the reemergence of old infectious diseases. One strategy employed to overcome these resistance mechanisms is the use of combination of drugs, such as β-lactams together with β-lactamase inhibitors. Several plant extracts have exhibited synergistic activity against microorganisms. This review describes in detail, the observed synergy and mechanism of action between natural products including flavonoids and essential oils and synthetic drugs in effectively combating bacterial, fungal and mycobacterial infections. The mode of action of combination differs significantly than that of the same drugs acting individually; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries.     

Multitarget therapy – The future of treatment for more than just functional dyspepsia

Since many years the concept of classical phytotherapy using herbal drug combinations with superior efficacy and lesser side effects in comparison with single isolated constituents of plant extracts has been repeatedly assessed clinically as well as pharmacologically. For this as multitarget therapy defined treatment lot of examples are presented. The exact mechanisms of action underlying these synergy effects is unknown. It could be explained by a multitarget action of compounds on a molecular level or partly by an improved resorption rate and a change of pharmacokinetic. Progress in the field of drug synergy research may lend with standardized plant extracts a new legitimacy and may open the chance to use extract combinations for the treatment of diseases which previously have been reserved for chemotherapeutics only.     

Natural products in modern life science

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific questions in Nature can be of value to increase the attraction for young students in modern life science.