Dynamic combinatorial chemistry platform for glycosaminoglycan binder discovery

Overview

This solution offers a dynamic combinatorial chemistry (DCC) platform for the discovery and optimization of molecular binders targeting glycosaminoglycans (GAGs), a class of biomacromolecules involved in numerous biological processes but notoriously difficult to address with conventional medicinal chemistry. GAG molecular recognition is critical for drug development in areas such as anticoagulation, inflammation, cancer metastasis, and extracellular matrix interactions. The DCC methodology uniquely integrates synthesis and screening into a single step by studying target-induced amplification from a dynamic library of potential binders connected through reversible covalent bonds. This enables rapid exploration of extensive structural diversity with minimal sample consumption and short timelines.

Technical specifications

Core methodology:

• Dynamic combinatorial chemistry using reversible covalent bonds to generate and screen libraries of potential GAG binders
• Target-induced amplification identifies the strongest binders from complex mixtures
• Building block selection tailored to the specific GAG target (heparin, heparan sulfate, chondroitin sulfate, or others)

Key features:

• Efficient binders to heparin identified with binding affinity (Kd) below micromolar, down to submicromolar range
• Biophysical validation using surface plasmon resonance (SPR), fluorescence titrations, and NMR
• Molecular modeling to confirm non-covalent binding interactions
• In vitro enzymatic assays correlating amplification factors with binding strength and biological activity
• Ex vivo and in vivo validation in mouse models demonstrating biological efficacy
• Capability to perform DCC experiments in living cells, demonstrated with chondroitin sulfate binders in the A549 cell line extracellular matrix

Technology readiness level

The platform has been validated through the discovery of efficient heparin binders with submicromolar affinity, confirmed by multiple biophysical techniques and supported by enzymatic, ex vivo, and in vivo assays. The methodology has also been extended to other GAG targets, including chondroitin sulfate in living cell environments. Future validation efforts focus on optimizing DCC assays for additional GAG targets such as heparan sulfate, executing screening experiments, preparative synthesis of amplified ligands, and comprehensive binding confirmation using SPR, NMR, fluorescence, and molecular modeling. The estimated project timeline is approximately two years.