Template-guided selection of RNA ligands using imine-based dynamic combinatorial chemistry

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Molecular Biology

Background:

• Discovering small molecules that bind to RNA targets is crucial for developing novel therapeutics.
• Dynamic combinatorial chemistry (DCC) offers a powerful platform for exploring chemical space and identifying ligands.
• Imine-based DCC, utilizing reversible imine bonds, presents a versatile approach for ligand discovery.

Purpose of the Study:

• To establish the utility of imine-based DCC for identifying non-covalent ligands targeting RNA.
• To investigate the reactivity of arylamines within DCC libraries for RNA ligand discovery.
• To demonstrate target-guided amplification of high-affinity binders using an amiloride-based DCC system.

Main Methods:

• Synthesis and characterization of an imine-based dynamic combinatorial library.
• Screening the library against specific RNA targets to identify binding events.
• Elucidating the chemical properties governing arylamine reactivity in the DCC system.
• Employing target-guided amplification to enrich and isolate potent RNA binders.

Main Results:

• The study successfully demonstrated the applicability of imine-based DCC for RNA ligand discovery.
• Key properties influencing arylamine reactivity in the context of RNA binding were elucidated.
• Target-guided amplification within an amiloride-based library led to the identification of tight-binding ligands.
• The developed methodology shows promise for discovering novel RNA-targeting agents.

Conclusions:

• Imine-based dynamic combinatorial chemistry is a viable strategy for discovering non-covalent RNA ligands.
• Understanding arylamine reactivity is essential for optimizing DCC library design for RNA targets.
• Target-guided amplification is an effective method for enriching potent binders from complex dynamic libraries.
• This approach holds significant potential for advancing RNA-targeted drug discovery.