Live-Cell-Templated Dynamic Combinatorial Chemistry.

Area of Science:

• Chemical Biology
• Drug Discovery
• Biomolecular Recognition

Background:

• Dynamic covalent chemistry (DCC) enables simultaneous screening and synthesis of ligands for biomolecular targets.
• In DCC, a template amplifies strongly binding species within a library of interconverting molecules.
• Traditional DCC methods often lack the complexity of a native biological environment.

Purpose of the Study:

• To pioneer the use of whole living cells as templates in dynamic combinatorial chemistry.
• To discover and characterize ligands that interact with the extracellular matrix of A549 lung cancer cells.
• To gain molecular insights into ligand-target interactions within a cellular context.

Main Methods:

• Employing A549 living cells as a template within a dynamic mixture of imines.
• Utilizing amplification of ligands that selectively bind to the cell's extracellular matrix.
• Characterizing ligand-matrix interactions using on-cell Nuclear Magnetic Resonance (NMR) spectroscopy.
• Integrating NMR, Surface Plasmon Resonance (SPR), and molecular dynamics (MD) simulations for detailed analysis.

Main Results:

• Successful amplification of polyamine ligands demonstrating strong binding to the A549 extracellular matrix.
• On-cell NMR experiments confirmed specific interactions between amplified ligands and cellular targets.
• Multi-technique approach (NMR, SPR, MD) provided comprehensive insights into the molecular recognition event.
• Demonstrated the feasibility and effectiveness of using whole living cells in DCC.

Conclusions:

• Whole living cells can serve as effective templates in dynamic combinatorial chemistry.
• This novel approach facilitates the discovery of bioactive molecules in a more biorelevant setting.
• The findings pave the way for developing new therapeutic strategies by targeting cellular components in their native environment.