Activatable Cell Penetrating Peptide–Peptide Nucleic Acid Conjugate via Reduction of Azobenzene PEG Chains,Journal of the American Chemical Society

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Activatable Cell Penetrating Peptide–Peptide Nucleic Acid Conjugate via Reduction of Azobenzene PEG Chains
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2014-09-08 , DOI: 10.1021/ja507547w
Soo Hyeon Lee ₁ , Elena Moroz ₁ , Bastien Castagner ₁ , Jean-Christophe Leroux ₁

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The use of stimuli-responsive bioactive molecules is an attractive strategy to circumvent selectivity issues in vivo. Here, we report an activatable cell penetrating peptide (CPP) strategy ultimately aimed at delivering nucleic acid drugs to the colon mucosa using bacterial azoreductase as the local reconversion trigger. Through screening of a panel of CPPs, we identified a sequence (M918) capable of carrying a nucleic acid analogue payload. A modified M918 peptide conjugated to a peptide nucleic acid (PNA) was shown to silence luciferase in colon adenocarcinoma cells (HT-29-luc). Reversible functionalization of the conjugate's lysine residues via an azobenzene self-immolative linkage abolished transfection activity, and the free CPP-PNA was recovered after reduction of the azobenzene bond. This activatable CPP conjugate platform could find applications in the selective delivery of nucleic acid drugs to the colon mucosa, opening therapeutic avenues in colon diseases.

中文翻译：

通过还原偶氮苯PEG链的可激活细胞穿透肽-肽核酸缀合物

刺激响应生物活性分子的使用是一种有吸引力的策略，可以规避体内选择性问题。在这里，我们报告了一种可激活的细胞穿透肽 (CPP) 策略，最终旨在使用细菌偶氮还原酶作为局部再转化触发器将核酸药物递送到结肠粘膜。通过筛选一组 CPP，我们确定了一个能够携带核酸类似物有效载荷的序列 (M918)。与肽核酸 (PNA) 缀合的修饰 M918 肽显示可以使结肠腺癌细胞 (HT-29-luc) 中的荧光素酶沉默。偶联物赖氨酸残基的可逆功能化通过偶氮苯自焚连接消除了转染活性，并且在偶氮苯键还原后回收了游离的 CPP-PNA。

更新日期：2014-09-08

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