Lung Fibrosis - Collagen I translation inhibitors
Fibrosis represents a large group of diseases that remains without effective treatment. It is caused when a wound healing process goes out of control and progresses into a continuing scarring process in the affected organs. The common denominator across fibrotic processes in different organs is over-production of Collagen Type I. By using our platform, we identify Collagen I translation inhibitors, compounds that are active in reducing the production of Collagen I. This is a novel strategy against fibrotic diseases in multiple organs.
Status
- Four distinct compound clusters with favorable SAR (structure-activity relationship) properties in hit-optimization
- We monitor Collagen I translation by using singular pairs of labeled tRNApro and tRNAgly isoforms
- A diverse library of 100,000 compounds was screened, generating a set of 20 million images. The resulting big data was analyzed by our cloud-based platform using proprietary image analysis and machine learning algorithms to identify “hits”, compounds that are actively reducing the production of Collagen I
- Hits were shown to be specific to Collagen I translation, not inhibiting general protein translation, they reduce Collagen I translation in human lung fibroblast cell lines and in primary human lung fibroblasts
- Hits undergoing optimization showed dose-dependent activity in reducing Collagen I accumulation in human lung fibroblasts, cell lines and primary cells (EC50 < 1 mM)
- Different compounds families are developed towards distinct fibrosis indications: Lung or Liver Fibrosis and Scleroderma
1. PSM Screen: Target-specific tRNA pair
2.3 million images generated per screen
Automatic generation of a clean FRET image
2. High content, cloud-based image analysis
Data generated for 54 million cells
90 different features
Total of 5 billion data points
3. Hit Identification: Big data analysis
4. Hits Optimization: Collagen I translation inhibitors
Collagen 1 protein translation was monitored in human lung fibroblasts using a Collagen 1-specific pair of labeled tRNAs (upper panel). PSM signal is depicted as yellow spots around cell nucleus (blue color). The first panel on the left shows control cells. In each of the next two panels, cells were incubated for 24 hours with different hit compounds from a 100K screen. In the lower panel, levels of accumulated Collagen 1 protein in cell cytoplasm is shown (green color). In compound-treated wells (5 days incubation), Collagen 1 levels are reduced, but not completely inhibited, reflecting modulation of collagen synthesis and not a complete shut off.