A Photoaffinity-Based Fragment-Screening Platform for Efficient Identification of Protein Ligands

Area of Science:

• Chemical biology
• Proteomics
• Drug discovery

Background:

• Genomic analyses increasingly identify novel disease-associated proteins.
• Validating these protein targets requires specific tool molecules (ligands) to demonstrate therapeutic potential.
• Current methods for ligand discovery are limited, hindering the use of genomic insights.

Purpose of the Study:

• To present a novel fragment-screening platform, PhotoAffinity Bits (PhABits), for efficient ligand discovery.
• To enable the covalent capture and profiling of fragment-protein interactions.
• To facilitate the development of novel therapeutics by identifying starting points for drug development.

Main Methods:

• Utilized a library of photoreactive fragments for covalent capture of fragment-protein interactions.
• Employed fragment screening as an efficient approach to explore chemical space.
• Developed hit profiling to determine potency and crosslinking sites.

Main Results:

• Successfully demonstrated the PhABit platform's ability to capture fragment-protein interactions.
• Enabled profiling of fragment hits for potency and crosslinking site identification.
• Established a pathway for developing hits into reporters for identifying novel therapeutics.

Conclusions:

• The PhABit platform provides a robust method for exploring chemical space and identifying novel protein binders.
• This platform is broadly applicable to new protein targets, accelerating therapeutic development.
• PhABits serves as a crucial tool for leveraging genomic discoveries into potential disease-modifying therapies.