Squaramide-Based 5′-Phosphate Replacements Bind to the DNA Repair Exonuclease SNM1A
Squaramide-Based 5′-Phosphate Replacements Bind to the DNA Repair Exonuclease SNM1A
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DOI：
10.1002/slct.201803375
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发表时间：
2018-12-06
期刊：
影响因子：
2.1
通讯作者：
McGouran, Joanna F.
中科院分区：
文献类型：
--
作者：
Durr, Eva-Maria;Doherty, William;McGouran, Joanna F.
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，但导致膜通透性较差。此外，该集团不能进行酶水解，这是其在治疗学和生物工具中使用的障碍。我们合成了N-氧基酰胺和5‘-末端方酰胺修饰的寡核苷酸作为磷酸盐替代品，并利用5’-核酸外切酶SNM1a对它们进行了生物学评价。方酰二胺的修饰显示出作为5‘-磷酸模拟物的最小识别能力；然而，观察到对SNM1A的适度抑制，推测是通过活性中心的金属配位发生的。它们在固相合成和被核酸外切酶识别后容易掺入，使方酰二胺成为中性的5‘-磷酸取代寡核苷酸。这项工作是第一个在寡核苷酸5‘末端修饰方二胺的例子，并可能利用修饰的寡核苷酸与SNM1A的金属中心结合。
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.