1. A Potent Conformation-Constrained Synthetic Peptide Mimic of a Homeodomain Selectively Regulates Target Genes in Cells.
- Author
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Ghosh B, Boila LD, Choudhury S, Mondal P, Bhattacharjee S, Pal SK, Sengupta A, and Roy S
- Subjects
- Amino Acid Sequence, Base Sequence, Biomimetic Materials chemical synthesis, Biomimetic Materials chemistry, Hematopoietic Stem Cells metabolism, Homeodomain Proteins chemical synthesis, Homeodomain Proteins chemistry, Humans, K562 Cells, Protein Binding, Protein Conformation, alpha-Helical, Protein Engineering, Transcription Factors chemical synthesis, Transcription Factors chemistry, Biomimetic Materials metabolism, DNA metabolism, Gene Expression Regulation genetics, Homeodomain Proteins metabolism, Transcription Factors metabolism
- Abstract
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.- Published
- 2018
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