Discovery of novel and highly potent XIAP-targeted peptide inhibitors using virtual screening

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Lung cancer presents a significant global therapeutic challenge.
• X-linked inhibitor of apoptosis protein (XIAP) overexpression drives cancer proliferation.
• Targeted XIAP inhibition offers a potential strategy to suppress tumor growth.

Purpose of the Study:

• To identify novel peptide inhibitors of XIAP.
• To evaluate the efficacy and safety of candidate peptides in preclinical models.
• To explore the mechanism of action for XIAP-targeted cancer therapy.

Main Methods:

• Virtual screening to identify XIAP-binding peptides.
• Biophysical assays (e.g., FP assay) to determine binding affinity and kinetics.
• Molecular dynamics simulations for structural stability analysis.
• In vitro assays for cellular permeability, metabolic stability, and antiproliferative activity.

Main Results:

• Five novel peptides with picomolar inhibitory activity against XIAP were identified.
• Peptide-5 demonstrated high binding affinity (Kd = 10.2 ± 0.5 pM) to the XIAP BIR3 domain.
• Peptide-5 exhibited excellent serum and metabolic stability, favorable cellular permeability, and potent antiproliferative effects on tumor cells without toxicity to normal cells.
• Peptide-5 modulated Bcl-2/Bax mRNA expression, suggesting activation of apoptotic signaling.

Conclusions:

• Peptide-5 is a highly potent XIAP inhibitor with promising therapeutic potential.
• This novel peptide demonstrates favorable pharmacokinetic properties and selective anti-tumor activity.
• Peptide-5 represents a promising candidate for the development of novel cancer treatments targeting XIAP.