在固相DNA编码文库合成中实现最大DNA回收率的考虑

IF 3.784 3区 化学 Q1 Chemistry
Alexander K. Price*, Brian M. Paegel*
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引用次数: 0

摘要

dna编码文库(DEL)技术使快速、经济的合成和探索新的化学空间成为可能。DEL合成的反应发展最近加快了步伐,特别强调确保反应不会损害编码DNA的完整性。然而,影响反应“DNA相容性”的因素仍然相对未知。我们研究了几种固相反应和编码条件,并确定了它们对DNA相容性的影响。最小化反应基团在DNA编码标签上的可及性的条件(切换溶剂、低温、双链编码标签)显著提高了相容性。我们在酰基沉积肽(ADEP1)片段的多步合成中展示了这种方法,该方法保存了73%的DNA,比标准条件提高了100倍。这些结果在多步反应序列中获得天然产物样支架的背景下尤其令人鼓舞,并且更广泛地强调了将DNA的生物物理性质和反应性与化学开发相协调以产生高质量支架文库的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Considerations for Achieving Maximized DNA Recovery in Solid-Phase DNA-Encoded Library Synthesis

Considerations for Achieving Maximized DNA Recovery in Solid-Phase DNA-Encoded Library Synthesis

DNA-encoded library (DEL) technology enables rapid, economical synthesis, and exploration of novel chemical space. Reaction development for DEL synthesis has recently accelerated in pace with a specific emphasis on ensuring that the reaction does not compromise the integrity of the encoding DNA. However, the factors that contribute to a reaction’s “DNA compatibility” remain relatively unknown. We investigated several solid-phase reactions and encoding conditions and determined their impact on DNA compatibility. Conditions that minimized the accessibility of reactive groups on the DNA encoding tag (switching solvent, low temperature, double-stranded encoding tag) significantly improved compatibility. We showcased this approach in the multistep synthesis of an acyldepsipeptide (ADEP1) fragment, which preserved 73% of DNA for a >100-fold improvement over canonical conditions. These results are particularly encouraging in the context of multistep reaction sequences to access natural product-like scaffolds and more broadly underscore the importance of reconciling the biophysical properties and reactivity of DNA with chemistry development to yield high-quality libraries of those scaffolds.

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来源期刊
ACS Combinatorial Science
ACS Combinatorial Science CHEMISTRY, APPLIED-CHEMISTRY, MEDICINAL
自引率
0.00%
发文量
0
审稿时长
1 months
期刊介绍: The Journal of Combinatorial Chemistry has been relaunched as ACS Combinatorial Science under the leadership of new Editor-in-Chief M.G. Finn of The Scripps Research Institute. The journal features an expanded scope and will build upon the legacy of the Journal of Combinatorial Chemistry, a highly cited leader in the field.
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