Constructing New Bioorthogonal Reagents and Reactions.
Constructing New Bioorthogonal Reagents and Reactions.
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DOI：
10.1021/acs.accounts.7b00606
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发表时间：
2018-05-15
影响因子：
18.3
通讯作者：
Prescher JA
中科院分区：
文献类型：
--
作者：
Row RD;Prescher JA
化学工具正在改变我们对生物分子和生命系统的理解。生物正交试剂（bioorthogonal reagents）是一种对大多数生物物种呈惰性的官能团，但可以选择性地与互补探针连接，甚至在活细胞和整个生物体中也是如此。这些工具的应用揭示了对生物分子结构和功能信息的基本新见解，这些信息往往超出了遗传方法的范围。在许多情况下，从生物正交探针获得的知识使人们能够提出新的问题，并进行创新研究。因此，这些工具的持续发展和应用有望改善我们对生物系统的看法，并促进新的发现。尽管在生物正交化学方面取得了几十年的成就，但仍然存在局限性。有几种试剂对于在细胞环境中使用来说太大或不够稳定。许多生物正交组也相互交叉反应，限制他们单一的任务。在这个账户中，我们描述了我们的工作，以解决生物正交工具箱中的一些空白。迄今为止，我们的努力主要集中在具有高度可调谐性的小试剂：环丙烯，三嗪和环丙烯酮。这些基序选择性地与互补试剂反应，它们的独特功能使生物学成为可能。该帐户由我们开发新型生物正交试剂和反应中出现的共同主题组织。首先，天然产物结构可以作为探针设计的有价值的起点。环丙烯、三嗪和环丙烯酮基序都存在于天然产物中，这表明它们在代谢上是稳定的，并且与各种生命系统相容。其次，微调生物正交试剂是必不可少的，他们成功地翻译到生物系统。不同的应用程序需要不同类型的探测器;因此，生成一个跨越反应性和稳定性连续体的工具集合仍然是一个重要的目标。我们已经使用了计算分析和机制的研究，以指导各种环丙烯和三嗪探针的优化。沿着这条路，我们确定了化学选择性的试剂，但最适合体外工作。另一些则具有足够的选择性和鲁棒性，可用于生物体。本报告的最后一节强调需要继续寻求新的试剂和反应。当生物正交化学必须协同使用时，存在挑战，因为许多生物正交化学利用类似的机制，不能同时使用。这些限制已经排除了许多多组分标记研究和其他生物学应用。除了探索独特的反应类型外，我们还依赖于机械和计算的见解来识别相互正交的反应集。机械上不同的，生物相容性反应的持续发展将进一步多样化的生物正交反应组合检查生物分子。
Chemical tools are transforming our understanding of biomolecules and living systems. Included in this group are bioorthogonal reagents – functional groups that are inert to most biological species, but can be selectively ligated with complementary probes, even in live cells and whole organisms. Applications of these tools have revealed fundamental new insights into biomolecule structure and function—information often beyond the reach of genetic approaches. In many cases, the knowledge gained from bioorthogonal probes has enabled new questions to be asked and innovative research to be pursued. Thus, the continued development and application of these tools promises to both refine our view of biological systems and facilitate new discoveries. Despite decades of achievements in bioorthogonal chemistry, limitations remain. Several reagents are too large or insufficiently stable for use in cellular environments. Many bioorthogonal groups also cross-react with one another, restricting them to singular tasks. In this Account, we describe our work to address some of the voids in the bioorthogonal toolbox. Our efforts to date have focused on small reagents with a high degree of tunability: cyclopropenes, triazines, and cyclopropenones. These motifs react selectively with complementary reagents, and their unique features are enabling new pursuits in biology. The Account is organized by common themes that emerged in our development of novel bioorthogonal reagents and reactions. First, natural product structures can serve as valuable starting points for probe design. Cyclopropene, triazine, and cyclopropenone motifs are all found in natural products, suggesting that they would be metabolically stable and compatible with a variety of living systems. Second, fine-tuning bioorthogonal reagents is essential for their successful translation to biological systems. Different applications demand different types of probes; thus, generating a collection of tools that span a continuum of reactivities and stabilities remains an important goal. We have used both computational analyses and mechanistic studies to guide the optimization of various cyclopropene and triazine probes. Along the way, we identified reagents that are chemoselective, but best suited for in vitro work. Others are selective and robust enough for use in living organisms. The last section of this Account highlights the need for the continued pursuit of new reagents and reactions. Challenges exist when bioorthogonal chemistries must be used in concert, given that many exploit similar mechanisms and cannot be used simultaneously. Such limitations have precluded many multi-component labeling studies and other biological applications. We have relied on mechanistic and computational insights to identify mutually orthogonal sets of reactions, in addition to exploring unique genres of reactivity. The continued development of mechanistically distinct, biocompatible reactions will further diversify the bioorthogonal reaction portfolio for examining biomolecules.
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