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A Potent Conformation-Constrained Synthetic Peptide Mimic of a Homeodomain Selectively Regulates Target Genes in Cells
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-07-02 00:00:00 , DOI: 10.1021/acschembio.8b00488 Basusree Ghosh 1 , Liberalis Debraj Boila 2 , Susobhan Choudhury 3 , Priya Mondal 1 , Sayan Bhattacharjee 4 , Samir Kumar Pal 3 , Amitava Sengupta 2 , Siddhartha Roy 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-07-02 00:00:00 , DOI: 10.1021/acschembio.8b00488 Basusree Ghosh 1 , Liberalis Debraj Boila 2 , Susobhan Choudhury 3 , Priya Mondal 1 , Sayan Bhattacharjee 4 , Samir Kumar Pal 3 , Amitava Sengupta 2 , Siddhartha Roy 1
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DNA, as a target for therapeutic intervention, remains largely unexplored. DLX-4, a homeodomain containing transcription factor, and its spliced isoforms play crucial roles in many aspects of cellular biochemistry and important roles in many diseases. A smaller peptide mimicking the homeodomain of the transcription factor DLX-4 was designed and synthesized by suitable conjoining of its modified DNA-binding elements. The peptide binds to DLX-4 target sites on the regulatory region of the globin gene cluster with native-like affinity and specificity in vitro. When conjugated to cell penetrating and nuclear localization sequences, it upregulated some of the genes repressed by DLX-4 or its isoforms, such as β- and γ-globin genes in erythropoietin-induced differentiating CD34+ human hematopoietic stem/progenitor cells with high specificity by competing with the respective binding sites. Engineered peptides mimicking DNA-binding domains of transcription factors offer the potential for creating synthetic molecules for directly targeting DNA sites with high specificity.
中文翻译：
Homeodomain的强构象约束合成肽模拟选择性调节细胞中的靶基因。
作为治疗干预目标的DNA基本上尚未开发。DLX-4是一个含有转录因子的同源结构域，其剪接的同工型在细胞生物化学的许多方面起着至关重要的作用，在许多疾病中也起着重要的作用。通过适当修饰其修饰的DNA结合元件，设计并合成了模仿转录因子DLX-4同源结构域的较小肽。该肽在体外以天然样的亲和力与球蛋白基因簇调控区域上的DLX-4靶位点结合。当与细胞穿透和核定位序列偶联时，它上调了由DLX-4或其同工型抑制的某些基因，例如促红细胞生成素诱导的分化CD34 +中的β-和γ-球蛋白基因。通过与各自的结合位点竞争而具有高特异性的人造血干/祖细胞。模仿转录因子DNA结合结构域的工程化肽为创建合成分子提供了潜力，该合成分子可直接以高特异性靶向DNA位点。
更新日期：2018-07-02
中文翻译：
Homeodomain的强构象约束合成肽模拟选择性调节细胞中的靶基因。
作为治疗干预目标的DNA基本上尚未开发。DLX-4是一个含有转录因子的同源结构域，其剪接的同工型在细胞生物化学的许多方面起着至关重要的作用，在许多疾病中也起着重要的作用。通过适当修饰其修饰的DNA结合元件，设计并合成了模仿转录因子DLX-4同源结构域的较小肽。该肽在体外以天然样的亲和力与球蛋白基因簇调控区域上的DLX-4靶位点结合。当与细胞穿透和核定位序列偶联时，它上调了由DLX-4或其同工型抑制的某些基因，例如促红细胞生成素诱导的分化CD34 +中的β-和γ-球蛋白基因。通过与各自的结合位点竞争而具有高特异性的人造血干/祖细胞。模仿转录因子DNA结合结构域的工程化肽为创建合成分子提供了潜力，该合成分子可直接以高特异性靶向DNA位点。
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