4.6 Article

A Potent Conformation-Constrained Synthetic Peptide Mimic of a Horneodomain Selectively Regulates Target Genes in Cells

Journal

ACS CHEMICAL BIOLOGY
Volume 13, Issue 8, Pages 2003-2009

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acschembio.8b00488

Keywords

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Funding

  1. JC Bose Fellowship
  2. DST, Govt. of India
  3. CSIR
  4. DBT [BT/PR13023/MED/31/311/2015]
  5. Ramalingaswami Fellowship
  6. UGC

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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 beta- and gamma-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.

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