We propose to test the hypothesis that it is possible to discover an oral pan-coronavirus (COV) drug which targets a conserved COV protein using high throughput screening. An oral Pan-COV drug is needed to treat expected future COV pandemics which could be as widespread and lethal as Covid19. Such a drug would also be useful to treat endemic COVs which cause serious disease in immunocompromised patients and to supplement current SARS-COV2 treatments. 

We will make use of 384-well plate cell imaging assays for replication of human coronaviruses COV-229E and COV-OC43 developed in the Abbvie-HMS collaboration to screen a 50,000 compound ICCB library for inhibition of COV-299E replication. After dose-response characterization and re-testing of purchased compounds, we will test the best picks on then test picks on COV-OC43 in house and SARS-COV2 via collaboration with a NEIDL BL3 lab. 

Our goal is to identify compounds with IC50 values of <10μM against one COV species, <30μM for all three COVs and <30μM for COV-229E in at least three cell lines. We will also require IC50s for inhibiting the growth of three lines more than 30-fold higher than anti-viral IC50s as preliminary evidence of lack of toxicity and eliminate compounds with lysosome-neutralizing activity. Stretch objectives include characterization of structure-activity relationships and preliminary characterization of cellular and molecular mechanisms of action of promising compounds. 

Funding

Funding Duration

July 1, 2024 - June 30, 2025

Funding level

Pilot

People

Principal Investigator

Timothy Mitchison

PhD
Hasib Sabbagh Professor of Systems Biology, Harvard Medical School