PNA-Based Dynamic Combinatorial Libraries (PDCL) and screening of lectins.

Area of Science:

• Biochemistry
• Chemical Biology
• Drug Discovery

Background:

• Dynamic combinatorial libraries (DCL) offer dynamic molecular assembly for ligand discovery.
• Current DCL methods using reversible covalent interactions face limitations in biomedical applications due to exchange reversibility and analytical challenges.
• Small molecule fragment deconvolution in DCL is analytically challenging.

Purpose of the Study:

• To develop a supramolecular approach for DCL using a constant PNA tag to direct fragment pairing.
• To overcome limitations of traditional DCL methods in drug discovery and biomedical research.
• To improve analytical deconvolution and achieve higher affinity ligand discovery.

Main Methods:

• Utilized a constant short PNA tag to direct combinatorial pairing of fragments.
• Employed fast exchange kinetics and cooperativity for library assembly.
• Applied matrix-assisted laser desorption/ionization (MALDI) for analytical deconvolution.
• Screened over 6,000 glycan assemblies targeting AFL, a lectin from pathogenic fungus.

Main Results:

• Achieved a 95 nM affinity for a glycan assembly targeting AFL.
• Demonstrated nearly three orders of magnitude improvement in affinity compared to the glycan alone (41 µM).
• The PNA tag facilitated efficient library selection and deconvolution.

Conclusions:

• The supramolecular PNA-tagged DCL approach enhances ligand discovery for protein targets.
• This method offers improved affinity and analytical tractability over traditional DCL techniques.
• The technology shows promise for drug discovery and biomedical research applications.