Orthogonal functionalisation of α-helix mimetics

Area of Science:

• Medicinal Chemistry
• Organic Chemistry
• Molecular Biology

Background:

• Alpha-helix (α-helix) mediated protein-protein interactions are crucial in biological processes.
• Inhibiting these interactions holds significant therapeutic potential.
• Developing small molecules that mimic or disrupt α-helix structures is a key challenge.

Purpose of the Study:

• To introduce a novel methodology for modifying N-alkylated aromatic oligoamide α-helix mimetics.
• To utilize 'click' chemistry for efficient and versatile modification of these mimetics.
• To investigate the impact of these modifications on the binding properties of p53/hDM2 inhibitors.

Main Methods:

• Synthesis of N-alkylated aromatic oligoamide α-helix mimetics.
• Application of 'click' chemistry for functionalization of the mimetics.
• Evaluation of binding affinities and modulation of interactions with target proteins (p53/hDM2).

Main Results:

• Successful modification of α-helix mimetics using 'click' chemistry.
• Demonstrated modulation of binding properties of the designed inhibitors.
• The modified mimetics showed altered selectivity and affinity towards p53/hDM2.

Conclusions:

• The developed 'click' chemistry approach provides a powerful tool for designing α-helix mimetics.
• This methodology enables fine-tuning of inhibitor binding properties for therapeutic applications.
• The modified p53/hDM2 inhibitors represent promising leads for further drug development.