基于合成生物学的安莎结构优化

Ansamycins are a family of potent macrolactams in that three wellknown drug leads were discovered from two hundreds of compounds. However, the drug development progress of this class of natural products was hampered by the drawbacks of their druggability such as low solubility and evident hepatotoxicity. Synthetic biology has many advantages over synthetic chemistry in optimizing the structures of complicated natural products. Moreover, ansamycins have complex mechanism of biosynthesis, which affords desired status for structural optimizations by synthetic biology. Thus, in this project, we aim to improve the druggability of ansamycins through structural optimizations by three different approaches: 1. manipulating the putative regulator genes to expand the structure diversity of ansamycins, 2. modifying biosynthetic genes to link up the interconversion of benzenic and naphthenic ansamycins, and 3. modifying the structures of ansamycins by the carbamoyltransferases and/or epoxidases. All three approaches will afford new ansamycins that will be screened for their antibacterial and antitumor activity, and evaluated for their hepatotoxicity. This project is significant in exploring new fields of medicinal chemistry of natural products, and new approaches to drug discovery and innovation.

安莎是一类生物活性显著的大环内酰胺，该家族仅有200余个成员，但是产生了3个著名的药物先导，即抗结核利福霉素、抗肿瘤格尔德霉素和美登木素。然而，其溶解性差和肝毒性强等成药性不足，限制了该家族的新药研发。合成生物学对于复杂天然产物的结构优化，与化学合成相比有诸多优势；而且，安莎生物合成机制的丰富多样性，为其合成生物学结构优化，提供了极为理想的条件。是故，本申请项目拟从三个方面开展安莎的结构优化：1. 改造安莎生物合成调控基因，拓展安莎的结构多样性；2. 改造安莎生物合成结构基因，实现苯安莎和萘安莎的相互转化；3. 利用安莎生物合成后修饰反应，如氨甲酰化和环氧化，改善安莎的成药性；并开展安莎新衍生物的抗细菌、抗肿瘤活性与肝脏毒性评价，为安莎类化合物的新药创制奠定基础，对拓展天然药物化学的新研究领域有借鉴意义。

安莎是一类生物活性显著的大环内酰胺，在该家族仅有的约300个成员中已经产生了3个著名的药物先导，即抗结核利福霉素、抗肿瘤格尔德霉素和美登木素。然而，由于溶解性差、肝毒性强等导致其成药性不足，限制了该家族的新药研发。合成生物学对于复杂天然产物的结构优化，与化学合成相比有诸多优势；而且安莎生物合成机制的丰富多样性，为其合成生物学结构优化提供了极为理想的条件。本项目从3个方面开展了安莎的合成生物学研究并取得了重要研究结果：1. 通过改造安莎生物合成调控基因，从3株放线菌中分离得到了27个骨架新颖的五酮安莎，丰富了五酮安莎的化学结构多样性；2. 通过敲除萘安莎产生菌Streptomyces sp. LZ35中编码羟基化酶的nas7基因，获得nas7缺失的突变株，从中成功分离得到13个结构新颖的苯安莎，并首次实现苯安莎和萘安莎的相互转化；3. 对安莎生物合成中氨甲酰化、丙氨酰化和环氧化等后修饰基因的改造，获得了结构多样的后修饰代谢产物，提高了美登醇的产量，为其工业生产奠定了重要基础；另外还开展了安莎新衍生物的抗细菌、抗肿瘤与抗感染等活性评价，为安莎类化合物的新药创制提供了先导化合物，对拓展天然药物化学的新研究领域有借鉴意义。