Beta-hairpin peptidomimetics: design, structures and biological activities

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Molecular Biology

Background:

• Protein structures provide blueprints for designing synthetic molecules (protein epitope mimetics, PEMs) that mimic biological interactions.
• Beta-hairpin motifs are versatile scaffolds for PEM design, enabling the recapitulation of epitope structure, conformation, and biological activity.

Purpose of the Study:

• To explore the potential of beta-hairpin scaffolds for creating synthetic molecules that mimic protein epitopes.
• To demonstrate the application of beta-hairpin PEMs in inhibiting protein-protein, protein-nucleic acid, and RNA interactions.

Main Methods:

• Designing and synthesizing beta-hairpin peptidomimetics by transplanting epitope sequences onto stabilizing templates.
• Utilizing combinatorial methods for library synthesis and screening to optimize PEM properties.
• Employing structural biology techniques (e.g., crystal structure, solution structures) to understand binding mechanisms.

Main Results:

• Beta-hairpin PEMs were designed to mimic antibody hypervariable loops, p53 alpha-helical epitopes, and HIV-1 RNA motifs (TAR and RRE).
• These mimetics demonstrated potent biological activities, including antimicrobial effects, inhibition of CXCR4, blocking p53-HDM2 interaction, and high-affinity binding to RNA.
• Structural studies revealed how protein surfaces adapt to hairpin mimetics, enhancing binding affinity.

Conclusions:

• Beta-hairpin scaffolds are effective for developing PEMs targeting diverse biological interactions.
• PEMs show potential as novel inhibitors for protein-protein, protein-nucleic acid, and RNA targets, with applications in drug discovery.
• This approach offers a promising avenue for developing new therapeutic agents, including antivirals.