DNA display II. Genetic manipulation of combinatorial chemistry libraries for small-molecule evolution.
DNA display II. Genetic manipulation of combinatorial chemistry libraries for small-molecule evolution.
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DOI：
10.1371/journal.pbio.0020174
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发表时间：
2004-07
期刊：
影响因子：
9.8
通讯作者：
Harbury PB
中科院分区：
文献类型：
--
作者：
Halpin DR;Harbury PB
生物体外选择技术，如RNA适体方法和mRNA展示，已被证明是具有新功能的工程分子的有力途径。这些技术是基于生物聚合物文库的迭代扩增，通过选择所需的功能特性。稀有的、有前途的化合物在不断复制的分子群体中经过多代的富集，并随后被鉴定出来。这种方法对DNA、RNA和多肽的限制使它们无法用于小分子发现。为了克服这一限制，我们已经指导了DNA“基因”组合化学文库的合成，使非生物分子物种的迭代扩增成为可能。在传统的分裂-池组合合成过程中，通过微分杂交，每个基因的DNA序列被读出并翻译成独特的小分子结构。这种“化学翻译”提供了比最先进的组合库复杂100万倍的合成化合物种群的实际访问。我们对106个非天然肽库进行了体外选择实验（迭代化学翻译、选择和扩增）。经过三代的进化，该文库聚合为一个高亲和力的蛋白质配体。基因编码各种合成转化的能力使得体外选择和潜在的无限化合物家族的进化成为可能，为药物发现、催化剂设计和材料科学“生物学”的发展开辟了新的途径。作者使用DNA“基因”来指导组合化学文库的合成，并在体外选择实验中表明可以开发出特定的药物
Biological in vitro selection techniques, such as RNA aptamer methods and mRNA display, have proven to be powerful approaches for engineering molecules with novel functions. These techniques are based on iterative amplification of biopolymer libraries, interposed by selection for a desired functional property. Rare, promising compounds are enriched over multiple generations of a constantly replicating molecular population, and subsequently identified. The restriction of such methods to DNA, RNA, and polypeptides precludes their use for small-molecule discovery. To overcome this limitation, we have directed the synthesis of combinatorial chemistry libraries with DNA “genes,” making possible iterative amplification of a nonbiological molecular species. By differential hybridization during the course of a traditional split-and-pool combinatorial synthesis, the DNA sequence of each gene is read out and translated into a unique small-molecule structure. This “chemical translation” provides practical access to synthetic compound populations 1 million-fold more complex than state-of-the-art combinatorial libraries. We carried out an in vitro selection experiment (iterated chemical translation, selection, and amplification) on a library of 106 nonnatural peptides. The library converged over three generations to a high-affinity protein ligand. The ability to genetically encode diverse classes of synthetic transformations enables the in vitro selection and potential evolution of an essentially limitless collection of compound families, opening new avenues to drug discovery, catalyst design, and the development of a materials science “biology.” The authors use DNA "genes" to direct the synthesis of combinatorial chemistry libraries, and show in an in vitro selection experiment that specific drugs can be developed
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影响因子：
9.8
作者：
Halpin DR;Lee JA;Wrenn SJ;Harbury PB
通讯作者：
Harbury PB
影响因子：
9.8
作者：
Halpin DR;Harbury PB
通讯作者：
Harbury PB
DOI：
10.1073/pnas.89.12.5381
发表时间：
1992-06-15
影响因子：
11.1
作者：
BRENNER, S;LERNER, RA
通讯作者：
LERNER, RA
影响因子：
15
作者：
Gartner, ZJ;Liu, DR
通讯作者：
Liu, DR
影响因子：
56.9
作者：
FORREST, S
通讯作者：
FORREST, S