Complex synthetic chemical libraries indexed with molecular tags

Area of Science:

• Chemical Biology
• Synthetic Chemistry
• Molecular Biology

Background:

• Combinatorial chemistry enables the synthesis of large molecular libraries.
• Identifying the structures of synthesized molecules is crucial for library utility.
• Current methods for tracking synthesis history can be complex.

Purpose of the Study:

• To develop a method for constructing and indexing a diverse peptide combinatorial library.
• To enable direct identification of individual library members based on their synthesis history.
• To demonstrate the selection of library members based on specific binding properties.

Main Methods:

• Synthesis of a peptide combinatorial library (117,649 members) on solid support (beads).
• Indexing of each bead with inert chemical tags encoding the reaction history in a binary code.
• Direct reading of the chemical tag code from single beads using electron capture capillary gas chromatography (ECCGC).
• Selection of library members based on binding affinity to a specific monoclonal antibody.

Main Results:

• Successful construction of a large, diverse peptide library with 117,649 unique members.
• Demonstration of accurate retrieval of synthesis history from individual beads using ECCGC.
• Validation of the method by correctly identifying and selecting library members that bind to a monoclonal antibody.

Conclusions:

• The described method provides an efficient and accurate way to construct, index, and identify members of peptide combinatorial libraries.
• This approach significantly enhances the utility of molecular libraries by enabling direct structure determination.
• The technology is applicable for screening and selecting molecules with desired binding properties, such as therapeutic antibodies.