Designer chemistry.
Designer chemistry.
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设计师化学。
DOI：
10.1111/1758-2229.12511
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发表时间：
2017
影响因子：
3.3
通讯作者：
Errington J
中科院分区：
文献类型：
--
作者：
Errington J
20世纪40年代和50年代通常被认为是抗生素发现的“黄金时代”。青霉素和链霉素的发现引发了人们对具有治疗价值的天然产物（NP）分子的识别和纯化的争夺。从化学的角度来看，纳米粒子具有有趣的特性，特别是在它们的大小，复杂性和通常的多个手性中心方面，所有这些都可以使意图制造类似物的药物化学家绝望地翻白眼。在大约50年的时间里，发现和描述了数千种天然产物小分子。当然，细菌并不是偶然携带制造这些分子的基因。我们可以假设，大多数是生物活性，提供了一个竞争优势的有机体在某些方面的利基，他们的运作。此外，它们在数百万年的进化中已经被磨练和优化。已确认的许多活性包括抗菌药物、抗真菌药、抗病毒药、抗癌药、抗寄生虫药、除草剂、他汀类药物和免疫抑制剂（纽曼和Cragg，2012）。虽然许多细菌和真菌产生生物活性NP分子，但最多产的生产者似乎具有丝状生长习惯，并且生活在土壤中。放线菌细菌是迄今为止研究得最好的，但很明显，我们对这些生物体的潜力才刚刚开始触及表面。尽管几乎所有的大型制药公司都在这一领域非常活跃，但到了新千年的黎明，大多数大公司都关闭或出售了他们的NP业务。主要原因有四个方面（银，2011年）。第一，重复发现相同的旧分子。“低垂的果实”已经消失，发现新分子变得越来越不容易。第二，分离NP分子的困难，NP分子通常仅以少量制备，经常与其他NP形成复杂的混合物，并且需要长时间且有时不可重现的挑剔生物体发酵。第三，化学结构的复杂性，特别是多个手性中心的存在，这往往使得全化学合成和类似物的制备，昂贵且耗时。最后，另一种多样性来源以“组合化学”的形式大张旗鼓地出现了（Mitchison，1994年）。其想法是采用易于合成和操作的小“药物样”分子，并通过组合合成方法产生大量相关类似物。这有望以更可控的方式创建不同化合物的库，重点也是药物化学家易于进一步推进和修改的分子。不幸的是，虽然已经取得了成功，但“combichem”方法产生了相对令人失望的结果，部分原因是与NP分子的复杂星座相比，以这种方式容易产生的化学多样性仍然非常有限，特别是在抗感染药物等领域。近年来，一些因素发生了变化，有望支持NP研究和应用的革命（沃尔什和菲施巴赫，2010年; Frasch等人，2013; Gomez-Escribano等人，2016; Katz and Baltz，2016）.首先，基因组测序揭示了NP的编码潜力几乎是无限的;大多数细菌至少产生一个NP小分子，并且来自放线菌等群体的许多细菌预计会产生数十种不同的分子。其次，至少对于细菌来说，负责NP合成的基因往往是聚集的，这样它们就可以...
The 1940s and 1950s are generally regarded as the ‘golden age’of antibiotic discovery. Discoveries of penicillin and streptomycin led to a scramble to identify and purify natural product (NP) molecules with therapeutic value. NPs had interesting properties from a chemical perspective, especially in terms of their size, complexity and often multiple chiral centres, all of which can make medicinal chemists intent on making analogues roll their eyes in despair. Over about 5 decades, literally thousands of natural product small molecules were discovered and described. Of course, bacteria don’t carry the genes for making these molecules by accident. We can presume that most are biologically active, providing a competitive advantage to the organisms in some aspect of the niche in which they operate. Also, that they have been honed and optimized for their function over millions of years of evolution. Some of the many activities that have been recognized include antibacterials, antifungals, antivirals, anticancers, antiparasitics, herbicides, statins and immunosuppressants (Newman and Cragg, 2012). Although many bacteria and fungi make bioactive NP molecules, the most prolific producers appear to have a filamentous growth habit, and live in the soil. The actinomycete bacteria are by far the best studied but it is becoming apparent that we have only begun the scratch the surface of the potential of these organisms. Although almost all of the major pharma companies had been active in this area, by the dawn of the new millennium, most of the big players had closed down or sold off their NP operations. The main reasons were fourfold (Silver, 2011). First, the repeated rediscovery of the same old molecules. The ‘low hanging fruit’had gone and discovery of new molecules was becoming less and less easy. Second, the difficulty of isolating NP molecules, which are often made only in small quantities, frequently in complex mixtures with other NPs, and requiring long and sometimes irreproducible fermentations with fastidious organisms. Third, the complexity of the chemical structures, particularly the presence of multiple chiral centres, which often made total chemical synthesis and the elaboration of analogues, expensive and time consuming. Finally, an alternative source of diversity had emerged, amid great fanfare, in the form of‘combinatorial chemistry’(Mitchison, 1994). The idea was to take small ‘drug like’molecules that were easy to synthesize and manipulate, and generate large numbers of related analogues by combinatorial synthetic methods. This promised to enable the creation of libraries of diverse compounds in a much more controlled manner, with a focus also on molecules that would be easy for medicinal chemists to take forward and modify further. Unfortunately, although there have been successes,‘combichem’approaches have yielded relatively disappointing outputs, partly because the chemical diversity that can be readily generated in this way remains quite limited, compared with the spectacularly complex constellation of NP molecules, especially in areas such as anti-infectives.Several factors have changed in recent times that promise to support a revolution in NP research and application (Walsh and Fischbach, 2010; Frasch et al., 2013; Gomez-Escribano et al., 2016; Katz and Baltz, 2016). First, genome sequencing has revealed that the coding potential for NPs is virtually unlimited; most bacteria make at least one NP small molecule and many bacteria from groups such as actinomycetes are predicted to make scores of different molecules. Second, at least for bacteria, the genes responsible for NP synthesis tend to be clustered, so that they can …
影响因子：
15
作者：
Walsh, Christopher T.;Fischbach, Michael A.
通讯作者：
Fischbach, Michael A.