Respiratory Syncytial Virus (RSV) viral protein translation inhibitors

Program
Assay Development
Hit Generation
Hit to lead
Preclinical
RSVViral Translation Inhibitors

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in infants, young children (up to the age of 5) and adults above the age of 65. In both children and adults, the disease is associated with high rate of hospitalization (~10% of patients per year), and with relatively high mortality rate (0.5% of infected patients). In the USA, RSV infection is responsible for 18% of all respiratory illness in children aged <5 years and 20% of all hospitalizations. Despite the significant medical need, there is no vaccine or effective treatment currently available for RSV infection.

Several compound clusters identified as reducing RSV translation and viral load in target cells.

A new strategy for the discovery of anti-viral drugs

Instead of directly targeting viral proteins which are prone to high mutation rate, we focus on intervention in host protein interactions with viral proteins, targeting cellular targets that viruses hijack and use to control the translation of their proteins. These targets are in the host cell and therefore are not impacted by the mutation of the virus itself. Targeting host proteins may give an additional advantage as these proteins may be required for propagation of other viruses, resulting in the development of pan-viral drugs.

Status

  • We monitor RSV’s immediate early genes (IEGs) translation by using singular pairs of labeled tRNAIle and tRNAIle isoforms
  • A diverse library of 100,000 compounds was screened, generating a set of 20 million images. - Big data analysis using our cloud-based software and proprietary image analysis and machine learning algorithms identified “hits”, compounds that inhibit the production of viral proteins
  • Hit compounds were shown to be specific to RSV translation, not inhibiting general protein translation
  • As a further validation, we showed with Immunofluorescence against RSV that hits compounds reduce the number of infected cells and/or reduce viral protein load

1. PSM Screen: Target-specific tRNA pair

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

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

3. Hit Identification: Big data analysis

4. Hits Optimization: RSV viral protein translation inhibitors

4. Hits Optimization: RSV viral protein translation inhibitors

Hits identified in 100K screen were incubated with cells and RSV at the time of infection. Twenty-four hours post-infection, RSV proteins were visualized by a specific antibody (green color). Control, infected cells are shown on the top, and three hits from the screen, from 3 different chemical scaffolds, are shown on the bottom. Compounds inhibit the number of infected cells as well as virus maturation, as exhibited by a punctuated pattern of RSV protein distribution in compound-treated cells.