中药新药的研究或许应该另辟蹊径？

陆 茵（中国药理学会中药与天然药物药理专业委员会委员，南京中医药大学教授，主要从事中药药理及中药新药研究。）

中药成分结构的多样性及作用靶点的复杂性是为了适应环境变化进化而来。“若无进化之光，生物学将毫无意义”，我们利用新达尔文主义（综合学说）的创建人杜布赞斯基的这一观点来诠释中药的药效物质基础的来源，或许会迎来中药新药研究的新思维、新方法。中药（尤以植物源性中药）结构种类多样的成分（群、族）是为了适应环境胁迫而不断进化的结果。进化所致机体受体的多样性和中药的多样性以及生物的复杂网络调控系统；中药为了应对微生物、昆虫等生物胁迫，分泌特殊物质（即功能性小分子物质）构成化学防御，这种外源性化学兴奋效应可以使得微生物或昆虫的胁迫耐受性增加；同时，为了抵御干旱、低氧、强紫外线、重金属等非生物胁迫，中药体内产生大量的结构多样的次生代谢产物。即使是在面对某一种环境胁迫时，植物形成的相互影响自我更新的适应性进化产物也并非是单一成分，而是由调控此胁迫多环节过程的结构多样性成分。迄今为止，已发现有几百种植物次生代谢产物具有抗真菌、抗细菌和抗病毒等作用。例如，Deavours等研究指出，苜蓿叶为了抵御茎点霉属（一种真菌病原体），苜蓿叶片中的芒柄花素苷和苜蓿素的含量会同时增加；另外，当植物受到昆虫啃食这一生物胁迫时，组织被破坏，释放出自身的或感受到植食性昆虫口腔分泌物中的诱导因子时，能迅速作出反应，合成毒性次生代谢产物，构成直接化学防御或合成挥发性次生代谢产物吸引植食性昆虫的天敌形成间接化学防御，以避免遭受过度啃食。如树胡椒在应对昆虫胁迫时，一方面会产生异松油烯导致昆虫拒食，另一方面则会产生黄樟素直接杀灭昆虫。虽然人对植物胁迫性进化的贡献较小，但鉴于物种适应性进化的保守性和趋同性，使得包括人类在内的动物与植物具有很高的生物相似性。除了合成和降解蛋白质、核酸、糖与脂质基本细胞生理过程一致外，一系列相互关联的信号通路在植物与动物体内中亦都保留了极高的相似性。例如，细胞色素CYP450酶系广泛进化保守性地存在于所有生物体，参与了化合物的生物合成、解毒和代谢等诸多过程；人体的AMP活化的蛋白激酶与植物中的SnRK1为同源物，这一同源的蛋白质激酶都能够通过感受细胞能量状态来维持真核细胞的ATP生成和消耗的平衡，来实现能量代谢的稳态；此外，人体内Nrf2作为一个核转录因子参与基因的抗氧化反应元件（ARE）调控元件的核心TGACG序列相结合，转录调控机体一系列抗氧化应激损伤和抗炎保护基因的表达。而在植物体内具有与ARE启动子调控元件序列及功能极其类似的As-1顺式作用元件，并具有与Nrf2结合域序列中等程度的相似的TGA转录子与之相结合。【The diversity of TCM composition and the complexity of its targets come from the adaptation to the evolution of environmental changes."Nothing in biology makes sense except in the light of evolution",said Dobzhansky,founder of the new-Darwinism(Theory of Synthesis),which can be used to interpret the source of material basis of pharma⁃codynamics of TCM.We may find new thoughts and approaches to the research of TCM.A wide variety of structural components(group,or family)of TCM,especially those plant-derived,are to adapt to the environmental stress and evolution.Evolution leads to the diversity of receptors in the human body,the variety of TCM as well as the complex biological network.In order to cope with biological threats,such as microorganisms and insects,Chinese medicinal herbs generate special substances(functional small molecules)to form chemical defenses.Such exogenous chemical hormesis can increase the stress toler⁃ance to microorganisms or insects;meanwhile,Chinese medicinal herbs produce a large number of structurally diverse secondary metabolites to resist drought,hypoxia,strong UV,heavy metals and other abiotic stresses.Even when faced with a specific environmental stress,the adaptive evolu⁃tionary products formed by plant interactions and self-renewal are not a single component but structural diversities that regulate the multi-link process of the stress.So far,hundreds of plant secondary metabolites have been found to have anti-fungal,anti-bacterial and anti-viral effects.For example,studies by Deavourset al.suggest that alfalfa leaves in response toPhoma(a fungal pathogen)can increase the levels of both monascus and alfalfa.Additionally,when plants are exposed to the threat of insects,the damaged tissue releases its own factors or sense factors secreted by herbivorous insects,which can quickly react and synthesize toxic secondary metabolites to constitute a direct chemical defense,or synthe⁃size volatile secondary metabolites to attract insects which are natural enemies of phytopha⁃gous insects to set up an indirect chemical defense against excessive gnawing.For example,when faced with insect stress,pepper trees synthesize terpinolenes that lead to insect anti⁃feedantactivity and produce safrole to kill insects directly.Despite the little contribution of humans to the stress evolution of plants,according to evolutionary conservatism and convergence,plants and animals,including humans,have high biological similarity.In addition to the synthesis and degradation of proteins,nucleic acids,saccha⁃rides and lipids,a series of interrelated signaling pathways are closely resembled in plants and animals.For example,evolutionary conservatism of the cytochrome CYP450 enzyme system is universal in all organisms and is involved in processes such as biosynthesis of compounds,detoxification and metabolism.The human AMP-activated protein kinase and plant SnRK1 are homologue.This homologous protein kinase can sense the state of cells and maintain the balance of ATP production or consumption in eukaryotic cells to achieve the homeostasis of energetic metabolism.In addition,the nuclear transcription factor Nrf2 binds to the core TGACG sequence in humans,which is the antioxidant response element(ARE)of a gene,to regulate the expres⁃sion of a series of anti-oxidative stress and anti-inflammatory genes.Additionally,in plants there are As-1 cis-acting elements that closely resemble the ARE promoter regulatory elements in sequence and function and are able to bind to TGA transcripts,which are moderately similar to the Nrf2 binding domain sequences.】

“生物系统并非逻辑的产物，而是进化所致，而进化是一个不太讲究精准的过程。生命并不会选择逻辑上的最佳设计来迎合新环境，而只在已经存在的基础上进行调整”。药用植物在应对环境胁迫所产生的防御物质，除了改善自身适应非生物性胁迫和对抗生物胁迫外，可以与人体产生优秀的生物相容性，用于人类疾病的治疗。这些防御物质（包括次生代谢产物）多为中药活性成分，而应对环境胁迫的中药活性成分可能就是靶向人体遗传协同致死靶点、实现药效协同倍增的药物组合来源。【"A biological system is not the product of logic but of evolution,an imprecise process.Life does not choose the logically best design to meet a new situation.Instead it adapts what already exists".In addition to improving their ability to adapt to abiotic stresses and to resist biotic stress,the defensive substances synthesized by medicinal plants in response to environmental stress have good biocompatibility with human bodies,so that they can be used for the treatment of human diseases.Most of these defensive substances(including secondary metabolites)are the active ingredients of TCM,which may be the source of drug combination that targets synergistic lethal molecules to achieve synergistic efficacy.】

上述植物进化及环境胁迫决定了中药中的有效成分具有对疾病靶标是低亲和力、结构种类多样、作用杂泛、生物利用度很低的特点。因此，中药新药发现也应契合这样的特点，合理设计研究方案，或许会大大推进中药新药研究的进程。你和我本就自在如风，何必拘泥于原有的中药新药研究思维和模式，带着一份好奇与梦想，另辟蹊径或许也是中药新药研究的一条路径！【Plant evolution and environmental stress mentioned above deter⁃mine the fact that active ingredients in TCM are characterized by low affinity,structural diversity,non-specificity and low bioavailability.Therefore,the discovery of new drugs of TCM should also take account of these features.Rational design of researchprogramsmaygreatlypromotethe research on TCM.Man is born free.Why get stuck in the original patterns and thinking?Curiosity and dreams can help us to find another good approach to the research of new drugs of TCM.】