24. Modulation of TREM2 Mechanism as a potential treatment for neurodegenerative diseases

Neurodegenerative diseases (ND) are debilitating, progressive conditions have awith great unmet medical needs. Investigational drugs targeting specific molecular pathologies have generally been unsuccessful in treating multiple different ND,. including Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s dDisease. Neuroinflammation (NI), especially the microglial (MG) component, has is a major factor in the pathogenesis of these diseases; however, broad-acting anti-inflammatory drugs have also been ineffective in clinical trials. Galectin-3 (Gal-3) is a unique, chimeric β-galactoside- binding lectin with a C-terminal carbohydrate-recognition domain (CRD) linked to an N-terminal a protein-binding domain, both of which are important to its pathological activities. Gal-3 has been reported to have a prominent role in inflammation and fibrosis including in several ND. Gal-3 is an endogenous ligand for the MG receptor TREM2 (triggering receptor expressed on myeloid cells 2), which is genetically associated with increased risk of multiple ND and is critical for the modulation of MG towards a neuroprotective phenotype. We hypothesize that modulate modulation of Gal-3 – TREM2 interactions with small, highly specific molecules that cross the blood-brain barrier (BBB) could be an efficacious treatment for inflammation in ND. Using an innovative computational analysis and in silico design, we have identified and synthesized small-molecule Gal-3 modulators. These include novel CRD CRD-specific galGal-3 inhibitors, as well non-carbohydrate small molecules targeting that target a newly discovered allosteric site on Gal-3. Some of the non-carbohydrate small molecules and that either inhibit Gal-3 activity while others or enhance Gal-3 binding activity to target proteins with high specificity and selectivity. These compounds are highly specific for Gal-3 and have no significant effect on other galectins, which decreases the likelihood of off-target effects. Some of the inhibitors block Gal-3 binding to TREM2 with an IC50 as low as 40nM and effectively reduce the production of inflammatory cytokines, such as IL-6 and MCP-1, in cell-based models. The low molecular weight (<600 Da) and other physical properties of these compounds favor BBB penetration and oral bioavailability. Validation and optimization of lead compounds, and efficacy studies in cell-based and preclinical models are underway. Targeting Gal-3 – TREM2 interactions with this novel class of Gal-3 ligands that modulate MG activation towards the neuroprotective state could be a highly effective anti-inflammatory treatment for ND. 

  • Rafael Nir
  •  Eliezer Zomer
  •  Olga Volpert
  •  Erez Eitan
  •  Elizabeth Griffith
  • SBH Sciences; Galectin Therapeutics