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The Development of CDC25A-Derived Phosphoseryl Peptides That Bind 14-3-3ε with High Affinities
Seraphine Kamayirese1, Sibaprasad Maity1, Laura A Hansen1
1Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, USA.
Abstract:
Overexpression of the 14-3-3ε protein is associated with suppression of apoptosis in cutaneous squamous cell carcinoma (cSCC). This antiapoptotic activity of 14-3-3ε is dependent on its binding to CDC25A; thus, inhibiting 14-3-3ε - CDC25A interaction is an attractive therapeutic approach to promote apoptosis in cSCC. In this regard, designing peptide inhibitors of 14-3-3ε - CDC25A interactions is of great interest. This work reports the rational design of peptide analogs of pS, a CDC25A-derived peptide that has been shown to inhibit 14-3-3ε-CDC25A interaction and promote apoptosis in cSCC with micromolar IC50. We designed new peptide analogs in silico by shortening the parent pS peptide from 14 to 9 amino acid residues; then, based on binding motifs of 14-3-3 proteins, we introduced modifications in the pS(174-182) peptide. We studied the binding of the peptides using conventional molecular dynamics (MD) and steered MD simulations, as well as biophysical methods. Our results showed that shortening the pS peptide from 14 to 9 amino acids reduced the affinity of the peptide. However, substituting Gln176 with either Phe or Tyr amino acids rescued the binding of the peptide. The optimized peptides obtained in this work can be candidates for inhibition of 14-3-3ε - CDC25A interactions in cSCC.
Insights
Researchers designed new peptide inhibitors to block the 14-3-3ε and CDC25A interaction, a key factor in suppressing apoptosis in cutaneous squamous cell carcinoma (cSCC). Optimized peptides show promise for cSCC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Overexpression of 14-3-3ε protein suppresses apoptosis in cutaneous squamous cell carcinoma (cSCC).
- The antiapoptotic function of 14-3-3ε is mediated by its interaction with CDC25A.
- Inhibiting the 14-3-3ε-CDC25A interaction is a potential therapeutic strategy for cSCC.
Purpose of the Study:
- To rationally design and optimize peptide inhibitors targeting the 14-3-3ε-CDC25A interaction.
- To evaluate the binding affinity and potential of modified peptides as therapeutic agents for cSCC.
Main Methods:
- In silico design of peptide analogs by shortening and modifying the parent pS peptide.
- Conventional and steered molecular dynamics (MD) simulations to study peptide binding.
- Biophysical methods to assess peptide-protein interactions.
Main Results:
- Shortening the pS peptide from 14 to 9 amino acids decreased its binding affinity.
- Substitution of Gln176 with Phenylalanine (Phe) or Tyrosine (Tyr) restored peptide binding affinity.
- Optimized peptides demonstrated potential for inhibiting 14-3-3ε-CDC25A interactions.
Conclusions:
- Modified peptide analogs, particularly those with Phe or Tyr substitutions, are effective inhibitors of 14-3-3ε-CDC25A binding.
- These optimized peptides represent promising candidates for developing novel therapeutic strategies against cSCC.
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