Small molecule binders of heparanase for PET imaging of lysosomal activity

Overview

This project develops small molecule binders targeting heparanase, a lysosomal protein involved in heparan sulfate turnover, for use as PET imaging ligands. Because heparanase is primarily located within lysosomes and the Golgi apparatus, selective binders enable accurate imaging of lysosomal activity, supporting monitoring of disease states associated with increased lysosomal function. The approach leverages fragment screening and structure-based drug design to produce high-affinity, highly selective compounds suitable for diagnostic imaging applications.

Technical specifications

Key features:

• E. coli expression system producing milligram quantities of heparanase protein, overcoming a field-wide bottleneck
• Fragment screening yielding more than 30 crystal structures with lead fragments exhibiting micromolar potency
• Multiple glycomimetic ligands with low micromolar affinity, some binding at distinct sites to increase imaging sensitivity
• Structural binding mechanisms characterized through X-ray crystallography and enzymatic assays
• Binding-based design strategy allowing use of fragments that bind remote from the active site, potentially minimizing off-target effects
• Validation pipeline using X-ray crystallography, established enzyme assays, and isothermal titration calorimetry (ITC)

Technology readiness level

The program is at an early-to-mid stage of preclinical development. Researchers have already expressed and purified heparanase in milligram quantities, screened small molecule libraries, and solved more than 30 co-crystal structures with lead fragments at micromolar potency. The next phase involves structure-based optimization to improve affinity and selectivity over a 1-2 year study period. Partnership is sought to support compound development toward high-affinity, selective heparanase binders suitable for PET ligand applications.