天然产物成药性的合成生物学改良
Synthetic biology approaches to improve druggability of natural products
- 合成生物学 2020年1卷第5期 页码：583-592
- 作者机构：
中国药科大学生命科学与技术学院化学生物学研究室，江苏 南京 211198
- 作者简介：
作者简介:王清（1994—），女，硕士研究生。研究方向：化学生物学。E-mail：499836857@qq.com
[ "陈依军（1962—），男，教授，主要从事药物合成生物学研究。E-mail：yjchen@cpu.edu.cn" ]
- 基金信息：“重大新药创制”国家科技重大专项(2019ZX09721001-004-001);国家自然科学基金(21778076)
DOI：10.12211/2096-8280.2020-019
中图分类号： Q 599收稿：2020-03-08，
修回：2020-09-23，
纸质出版：2020-10-31
- 稿件说明：
移动端阅览
王清, 陈依军. 天然产物成药性的合成生物学改良[J]. 合成生物学, 2020, 1(5): 583-592
WANG Qing, CHEN Yijun. Synthetic biology approaches to improve druggability of natural products[J]. Synthetic Biology Journal, 2020, 1(5): 583-592
王清, 陈依军. 天然产物成药性的合成生物学改良[J]. 合成生物学, 2020, 1(5): 583-592 DOI： 10.12211/2096-8280.2020-019.
WANG Qing, CHEN Yijun. Synthetic biology approaches to improve druggability of natural products[J]. Synthetic Biology Journal, 2020, 1(5): 583-592 DOI： 10.12211/2096-8280.2020-019.
摘要
微生物和植物来源的天然产物结构复杂多样，具有抗感染、抗肿瘤、免疫抑制等多种活性，是现代临床治疗药物的重要来源之一。然而，大部分天然产物存在水溶性差、活性不强、结构类似物多以及可及性受限等问题，难以通过简单的化学修饰和改造解决，极大限制了天然产物的成药性及其后续研发。综合基因工程、代谢工程、基因组学、系统生物学、合成化学和计算生物学等学科的合成生物学，为改善天然产物的成药性提供了新机遇。本文针对限制天然产物成药的主要因素，概述了近年来利用合成生物学方法与策略在提高天然产物成药性方面取得的研究进展。通过理性分析天然产物的构效关系、挖掘合成和调控元件、构建系列反应模块和人工合成体系、筛选并优化底盘生物等策略，实现了多种天然产物来源药物或前体在“细胞工厂”中的定向、高效合成。与此同时，合成生物学技术也衍生了结构多样和性质改良的生物活性分子和潜在新药。随着合成生物学、药学和信息科学等方面的发展，可以预见提高和改善天然产物成药性的研究将会进入一个崭新的时代。
Abstract
As an important source of clinical medicine and drug candidates
natural products originated from microorganisms and plants have a variety of biological activities
such as anti-infection
anticancer
immunosuppression and others. However
the physiochemical properties of natural products are usually not favorable for drug discovery and development
which has seriously limited the development of natural products for clinical applications. These hurdles include low aqueous solubility
lower potency
complexed structural analogs
and limited availability. Because all drugs should possess certain degree of aqueous solubility
the inherited low aqueous solubility of natural products markedly limits their druggability. Meanwhile
the efficacy of natural products is generally low
which requires significant improvements for therapeutic usefulness. Furthermore
the accumulation of various structural analogs of natural products leads to the difficulty of quality control for desired natural products. Moreover
in many cases
natural products are easily obtained or accessed for preclinical and clinical evaluations and subsequent clinical supply. Nevertheless
traditional strategy for natural product isolation has resulted in highly repeated rediscovery and the waste of time and resources
failing to deliver valuable bioactive leads and drug candidates. Recently
synthetic biology has become an emerging and valuable tool to address these limitations. Through the combination of genetic engineering
metabolic engineering
bioinformatics
systems biology
synthetic organic chemistry and computational biology
synthetic biology has been explored to improve various properties of natural products.In this review
we focus on the major factors that hinder the druggability of natural products and briefly summarize the progress made by approaches of synthetic biology in recent years. Based on structure-activity analysis
the structures of natural products can be modified or optimized by enzymes with different functions to produce favorable derivatives. Meanwhile
the manipulation of the synthetic and regulatory elements
the construction of a series of modules and the optimization of metabolic fluxes can significantly promote the production of natural product derived molecules. Moreover
de novo design of biosynthetic pathways under artificial regulation of the transcription and metabolism in coupling with suitable hosts and heterologous expression can further expand the biosynthetic potential towards natural products for their druggability. Given the diversity of structure and activity
natural products will continue to be an important source of bioactive compounds and new drugs in the future. With the rapid and prosperous development of synthetic biology technologies
together with the assistance of pharmaceutical sciences and computational technologies
a new era of natural product discovery and engineering can be foreseen.
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references
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