Topologically Tunable α-Helix Mimetics for Targeting Protein-Protein Interactions

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Organic Synthesis

Background:

• Protein-protein interactions (PPIs) are crucial in biological processes.
• Mimicking alpha-helical conformations at PPI interfaces is challenging.
• The BH3 domains of Bcl-2 proteins are key targets for cancer therapy.

Purpose of the Study:

• To develop a novel scaffold for replicating diverse alpha-helical conformations.
• To create customizable alpha-helix mimetics using N,N'-diphenyl-4,4'-biphenyldicarboxamide.
• To design inhibitors targeting anti-apoptotic Bcl-2 family proteins.

Main Methods:

• Design and synthesis of topologically tunable biphenyl scaffolds.
• Evaluation of scaffolds for mimicking BH3 domains of Bcl-2 proteins.
• Modification of substituents to achieve pan-active and selective inhibition.

Main Results:

• A library of N,N'-diphenyl-4,4'-biphenyldicarboxamide scaffolds was synthesized.
• Scaffolds successfully mimicked a wide range of helical surfaces.
• Developed both pan-active and selective inhibitors of anti-apoptotic Bcl-2 proteins with distinct binding profiles.

Conclusions:

• The developed biphenyl scaffold is a powerful tool for mimicking natural alpha-helices.
• This approach allows for the precise replication of subtle conformational differences.
• Enables the development of targeted inhibitors for Bcl-2 family proteins.