中藥新藥的研究或許應(yīng)該另辟蹊徑？

陸 茵（中國藥理學會中藥與天然藥物藥理專業(yè)委員會委員，南京中醫(yī)藥大學教授，主要從事中藥藥理及中藥新藥研究。）

中藥成分結(jié)構(gòu)的多樣性及作用靶點的復雜性是為了適應(yīng)環(huán)境變化進化而來?！叭魺o進化之光，生物學將毫無意義”，我們利用新達爾文主義（綜合學說）的創(chuàng)建人杜布贊斯基的這一觀點來詮釋中藥的藥效物質(zhì)基礎(chǔ)的來源，或許會迎來中藥新藥研究的新思維、新方法。中藥（尤以植物源性中藥）結(jié)構(gòu)種類多樣的成分（群、族）是為了適應(yīng)環(huán)境脅迫而不斷進化的結(jié)果。進化所致機體受體的多樣性和中藥的多樣性以及生物的復雜網(wǎng)絡(luò)調(diào)控系統(tǒng)；中藥為了應(yīng)對微生物、昆蟲等生物脅迫，分泌特殊物質(zhì)（即功能性小分子物質(zhì)）構(gòu)成化學防御，這種外源性化學興奮效應(yīng)可以使得微生物或昆蟲的脅迫耐受性增加；同時，為了抵御干旱、低氧、強紫外線、重金屬等非生物脅迫，中藥體內(nèi)產(chǎn)生大量的結(jié)構(gòu)多樣的次生代謝產(chǎn)物。即使是在面對某一種環(huán)境脅迫時，植物形成的相互影響自我更新的適應(yīng)性進化產(chǎn)物也并非是單一成分，而是由調(diào)控此脅迫多環(huán)節(jié)過程的結(jié)構(gòu)多樣性成分。迄今為止，已發(fā)現(xiàn)有幾百種植物次生代謝產(chǎn)物具有抗真菌、抗細菌和抗病毒等作用。例如，Deavours等研究指出，苜蓿葉為了抵御莖點霉屬（一種真菌病原體），苜蓿葉片中的芒柄花素苷和苜蓿素的含量會同時增加；另外，當植物受到昆蟲啃食這一生物脅迫時，組織被破壞，釋放出自身的或感受到植食性昆蟲口腔分泌物中的誘導因子時，能迅速作出反應(yīng)，合成毒性次生代謝產(chǎn)物，構(gòu)成直接化學防御或合成揮發(fā)性次生代謝產(chǎn)物吸引植食性昆蟲的天敵形成間接化學防御，以避免遭受過度啃食。如樹胡椒在應(yīng)對昆蟲脅迫時，一方面會產(chǎn)生異松油烯導致昆蟲拒食，另一方面則會產(chǎn)生黃樟素直接殺滅昆蟲。雖然人對植物脅迫性進化的貢獻較小，但鑒于物種適應(yīng)性進化的保守性和趨同性，使得包括人類在內(nèi)的動物與植物具有很高的生物相似性。除了合成和降解蛋白質(zhì)、核酸、糖與脂質(zhì)基本細胞生理過程一致外，一系列相互關(guān)聯(lián)的信號通路在植物與動物體內(nèi)中亦都保留了極高的相似性。例如，細胞色素CYP450酶系廣泛進化保守性地存在于所有生物體，參與了化合物的生物合成、解毒和代謝等諸多過程；人體的AMP活化的蛋白激酶與植物中的SnRK1為同源物，這一同源的蛋白質(zhì)激酶都能夠通過感受細胞能量狀態(tài)來維持真核細胞的ATP生成和消耗的平衡，來實現(xiàn)能量代謝的穩(wěn)態(tài)；此外，人體內(nèi)Nrf2作為一個核轉(zhuǎn)錄因子參與基因的抗氧化反應(yīng)元件（ARE）調(diào)控元件的核心TGACG序列相結(jié)合，轉(zhuǎn)錄調(diào)控機體一系列抗氧化應(yīng)激損傷和抗炎保護基因的表達。而在植物體內(nèi)具有與ARE啟動子調(diào)控元件序列及功能極其類似的As-1順式作用元件，并具有與Nrf2結(jié)合域序列中等程度的相似的TGA轉(zhuǎn)錄子與之相結(jié)合?！綯he 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.】

“生物系統(tǒng)并非邏輯的產(chǎn)物，而是進化所致，而進化是一個不太講究精準的過程。生命并不會選擇邏輯上的最佳設(shè)計來迎合新環(huán)境，而只在已經(jīng)存在的基礎(chǔ)上進行調(diào)整”。藥用植物在應(yīng)對環(huán)境脅迫所產(chǎn)生的防御物質(zhì)，除了改善自身適應(yīng)非生物性脅迫和對抗生物脅迫外，可以與人體產(chǎn)生優(yōu)秀的生物相容性，用于人類疾病的治療。這些防御物質(zhì)（包括次生代謝產(chǎn)物）多為中藥活性成分，而應(yīng)對環(huán)境脅迫的中藥活性成分可能就是靶向人體遺傳協(xié)同致死靶點、實現(xiàn)藥效協(xié)同倍增的藥物組合來源?！?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.】

上述植物進化及環(huán)境脅迫決定了中藥中的有效成分具有對疾病靶標是低親和力、結(jié)構(gòu)種類多樣、作用雜泛、生物利用度很低的特點。因此，中藥新藥發(fā)現(xiàn)也應(yīng)契合這樣的特點，合理設(shè)計研究方案，或許會大大推進中藥新藥研究的進程。你和我本就自在如風，何必拘泥于原有的中藥新藥研究思維和模式，帶著一份好奇與夢想，另辟蹊徑或許也是中藥新藥研究的一條路徑！【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.】