天然产物成药性的合成生物学改良

Synthetic biology approaches to improve druggability of natural products

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。

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.