Squaramide‐Based 5’‐Phosphate Replacements Bind to the DNA Repair Exonuclease SNM1A,ChemistrySelect

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Squaramide‐Based 5’‐Phosphate Replacements Bind to the DNA Repair Exonuclease SNM1A
ChemistrySelect ( IF 1.9 ) Pub Date : 2018-12-04 , DOI: 10.1002/slct.201803375
Eva-Maria Dürr ₁ , William Doherty ₁ , Sook Y Lee _{2,

3} , Afaf H El-Sagheer _{3,

4} , Arun Shivalingam ₃ , Peter J McHugh ₂ , Tom Brown ₃ , Joanna F McGouran ₁

Affiliation

Phosphate groups are often crucial to biological activity and interactions of oligonucleotides, but confer poor membrane permeability. In addition, the group's lability to enzymatic hydrolysis is an obstacle to its use in therapeutics and in biological tools. We present the synthesis of N‐oxyamide and squaramide modifications at the 5’‐end of oligonucleotides as phosphate replacements and their biological evaluation using the 5’‐exonuclease SNM1A. The squaryl diamide modification showed minimal recognition as a 5’‐phosphate mimic; however, modest inhibition of SNM1A, postulated to occur through metal coordination at the active site, was observed. Their facile incorporation after solid‐phase synthesis and recognition by the exonuclease makes squaryl diamides attractive neutral 5’‐phosphate replacements for oligonucleotides. This work is the first example of squaryl diamide modifications at the 5’‐terminal position of oligonucleotides and of the potential use of modified oligonucleotides to bind to the metal center of SNM1A.

中文翻译：

基于方酰胺的 5'-磷酸替代物与 DNA 修复核酸外切酶 SNM1A 结合

磷酸基团通常对寡核苷酸的生物活性和相互作用至关重要，但膜渗透性较差。此外，该基团对酶水解的不稳定性是其在治疗和生物工具中使用的障碍。我们介绍了在寡核苷酸 5' 端合成N-羟基酰胺和方酰胺修饰作为磷酸盐替代物，并使用 5'-核酸外切酶 SNM1A 对其进行生物学评估。方酰基二酰胺修饰显示出对 5'-磷酸模拟物的最低识别度；然而，观察到对 SNM1A 的适度抑制，推测是通过活性位点的金属配位而发生的。固相合成和核酸外切酶识别后，它们很容易掺入，使得方酰基二酰胺成为寡核苷酸有吸引力的中性 5'-磷酸替代品。这项工作是在寡核苷酸 5' 末端位置进行方酰基二酰胺修饰以及修饰寡核苷酸与 SNM1A 金属中心结合的潜在用途的第一个例子。

更新日期：2018-12-04

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