Small Molecules Antagonists Of Toll Like Receptor 9 For Treatment Of viral infections, dermatologic, autoimmune and inflammatory diseases

Goldblum Amiram, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research
Zapstein Maria, HUJI, School of Medicine - IMRIC, School of Pharmacy- Institute for Drug Research


  • Toll-like receptors (TLRs) have been implicated in several autoimmune and inflammatory diseases, including cancer, diabetes, cardiovascular disease, atherosclerosis, Alzheimer’s disease, and chronic neuropathic pain.
  • Currently, most of these life-threatening diseases do not have any treatments available in the market, representing unmet medical needs.
  • Three-dimensional structural data showing the ligand recognition mechanisms of all human TLRs (except for TLR10) have been deposited in public domains and encourage the development of TLR modulators (agonists and antagonists) to achieve various therapeutic goals.

Our Innovation

A novel immune modulating therapeutics based on 18 small molecules antagonists candidates newly discovered

  • Modulate immune response
  • Block multiple TLRs
  • Can be activated by endogenous molecules
  • Can be activated by low molecular weight synthetic compounds

Applications for use:

  • Multi-targeted drugs development with simpler pharmacokinetics, lower drug resistance and greater dosing flexibility than traditional “one target-one drug”, “cocktails drugs” and “linked drugs”.
  • New drugs against viral infections, dermatologic, autoimmune and inflammatory diseases
  • Discovery of novel and different molecular active structures. 


  • Human TLRs can elicit overlapping yet distinct immune responses because of their ability to recognize an overlapping set of molecular patterns. Therefore, potent poly TLR antagonists need to be developed to block multiple TLRs.
  • A cell-based assay that mimics the innate immune system that includes all 10 human TLR-receptors was developed, screening 1.8 million molecules, providing 68 top candidates which were evaluated in an assay based on TLR9.  
  • The process includes TLR9 data selection and preparation, followed by ISE algorithm method, MCC scoring method, virtual screening and in-vitro tests on cell-line.  
  • Further candidate improvement was done using applicability domain filtering and solubility filtering.


Fig. 1: Schematic representation of the assay for TLR9 compound screening. Both antagonist and the specific ligand CpG ODN are added to the cell line leading to a blocking of TLR9.



Patent Status

Granted US 11,104,677

Contact for more information:

Mel Larrosa
VP Business Development Healthcare