组合生物学在药物研究中的应用进展

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摘要

天然产物具有结构多样性和宽泛的生物活性，是宿主细胞的次级代谢产物，而新药的主要来源是化学合成的结构类似物。由于基因改良的异源宿主能高效表达组合生物合成途径，增加产物的浓度，降低药物成本，故它是一种获得天然产物类似物的环境友好型的方式。讨论了组合生物合成的3种主要策略：前体-定向的生物合成；酶-水平的修饰，包括整个功能域、模块和亚基的交换，定点诱变和定向进化；途径水平的重组。提出组合生物合成利用底物宽泛性、酶工程及其催化的途径获得新型非天然的自然产物，使潜在化合物结构更加多样化；需要高通量筛选方法筛选大量候选化合物，并用计算机方法结合结构-生物活性来分析进行优化设计，以确保其获得所需的活性，进一步探讨酶的动力学和机制以及代谢途径。

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	李彦美
	王娅莉
	班璐

关键词 ：组合生物合成, 天然产物, 聚酮合酶, 非核糖体肽合成酶

Abstract：

Natural products with structural diversity and broad biological activities are the secondary metabolites of host cells, in contrast, the main sources of new drugs are chemical synthesis analogues. Since genetically modified heterologous hosts can efficiently express the pathway of combinatorial biosynthesis, increase the concentration of the products and reduce the costs, it is a environmental friendly way to obtain natural product analogues. Three strategies of combinatorial biosynthesis are discussed, they are: precursor-directed biosynthesis; enzyme-level modification, including the exchange of function domains, modules and subunits, site-specific mutagenesis and directed evolution; pathway-level recombination. Combinatorial biosynthesis using the broadness of substrate, enzyme engineering and catalyzing way to obtain new unnatural natural products and the structure of potential compounds become more diverse. High-throughput synergy screening methods are needed urgently to screen large amount of candidate compounds, the computational methods and structure-bioactivity analyses are combined together to conduct optimal design and then to ensure the desired activities are achieved. And the dynamics, mechanisms and the metabolic pathways of enzyme are further discussed.

Key words： combinatorial biosynthesis natural product polyketide synthase nonribosomal peptide synthetases

作者简介: 李彦美（1986—），女，河北衡水人，助理工程师。 E-mail：ymleecpu@hotmail.com

引用本文:

李彦美，王娅莉，班璐. 组合生物学在药物研究中的应用进展[J]. 煤炭与化工, 2015, 38(7): 30-32. LI Yan-mei, WANG Ya-li, BAN Lu. Application Progress of Combinatorial Biology in Drug Research. CCI, 2015, 38(7): 30-32.

链接本文:

http://www.mtyhg.com.cn/CN/ 或 http://www.mtyhg.com.cn/CN/Y2015/V38/I7/30

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