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 rates of hospitalization (~10% of patients per year), and with relatively high mortality rates (0.5% of infected patients). In the U.S., 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.

Three compound series were identified for 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 target the virus’ ability to translate its mRNA. Cellular protein translation machinery is hijacked by the virus, and we target this host-virus interaction.

Status

  • We monitor RSV’s immediate early genes (IEGs) translation by using a signature pair of labeled tRNA 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,” which are compounds that inhibit the production of viral proteins.
  • Hit compounds were shown to be specific to RSV translation and did not inhibit general protein translation.
  • Optimized hits reduced RSV early gene expression in a dose-dependent manner.

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

Compounds inhibit RSV protein production in a cell-independent manner. Compounds from two different chemical series were incubated with RSV-infected HeLa or A549 cells (upper and lower panels, respectively), and viral proteins were detected 24 hours later.