Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine.
Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine.
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DOI：
10.1021/acs.jmedchem.9b00246
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发表时间：
2019-04
影响因子：
7.3
通讯作者：
Audrey E. Ynigez-Gutierrez;B. Bachmann
中科院分区：
文献类型：
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作者：
Audrey E. Ynigez-Gutierrez;B. Bachmann
从天然来源（包括细菌、真菌和植物）中分离出的分子是一种长期存在的治疗来源，今天继续增加我们的药物库。尽管它们在临床上的效力和突出性，复杂的天然产品往往表现出许多阻碍其作为治疗剂的发展的责任，这可能是目前远离天然产品发现，研究和开发的趋势的部分原因。然而，合成生物学和有机合成的进步激发了新一代天然产物化学家去解决强大的未开发支架。在这个角度来看，我们将介绍案例研究，展示历史和当前的重点是通过生物合成基因簇操作，全合成，半合成或这些方法的组合，对天然产物支架进行有针对性的，但显着的变化，重点是增加活性，降低毒性，或改善化学和药理学特性。
Molecules isolated from natural sources including bacteria, fungi, and plants are a long-standing source of therapeutics that continue to add to our medicinal arsenal today. Despite their potency and prominence in the clinic, complex natural products often exhibit a number of liabilities that hinder their development as therapeutics, which may be partially responsible for the current trend away from natural product discovery, research, and development. However, advances in synthetic biology and organic synthesis have inspired a new generation of natural product chemists to tackle powerful undeveloped scaffolds. In this Perspective, we will present case studies demonstrating the historical and current focus on making targeted, but significant, changes to natural product scaffolds via biosynthetic gene cluster manipulation, total synthesis, semisynthesis, or a combination of these methods, with a focus on increasing activity, decreasing toxicity, or improving chemical and pharmacological properties.