Disulfide-constrained peptide scaffolds enable a robust peptide-therapeutic discovery platform

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Peptides are promising therapeutic agents but often lack stability.
• Disulfide-constrained peptides (DCPs) offer enhanced chemical and physical stability.
• DCPs provide drug-like scaffolds amenable to engineering.

Purpose of the Study:

• To establish a robust platform for discovering peptide therapeutics using DCP scaffolds.
• To evaluate the platform's effectiveness for functional hit discovery.
• To demonstrate hit-to-lead progression for therapeutic candidates.

Main Methods:

• Construction of diverse phage display libraries using seven different DCP scaffolds (2 x 10^11 diversity).
• Selection and synthesis of peptides from DCP libraries.
• Affinity maturation strategies applied to identified binders.

Main Results:

• A high hit rate for functional discovery, comparable to synthetic antibody libraries.
• Generation of functional HtrA1 protease inhibitors.
• Optimization of weak Notch2 binders from micromolar to nanomolar affinity.

Conclusions:

• The developed platform is effective for discovering and optimizing peptide therapeutics.
• DCPs serve as valuable scaffolds for creating stable and potent peptide drugs.
• The platform facilitates a viable hit-to-lead progression for drug development.