Antiviral Drug Screen of Kinase inhibitors Identifies Cellular Signaling Pathways Critical for SARS-CoV-2 Replication
drug discovery/repurposing virology
Authors:Gustavo Garcia Jr. et al
Link to paper:https://doi.org/10.1101/2020.06.24.150326
Tags: Drug discovery/Drug repurpose, Virology
High-throughput screening of 430 protein kinase inhibitors targeting SARS-CoV-2 infection revealed 34 compounds capable of inhibiting viral cytopathic effects.
Drug validation in human cells highlights potential of Berzosertib, which is in phase 2 clinical trials for cancer treatment.
Berzosertib is a selective inhibitor of DNA damage response pathway Serine/threonine-protein kinase ATR, highlighting the role of this pathway in viral replication.
SARS-CoV-2 infectious cell culture system was established and used for high throughput drug screening of kinase inhibitors. 430 inhibitors tested via scoring/imaging of the viral cytopathic effects, and most hit compounds found to target a limited set of kinases and pathways; mainly the mTOR-PI3K-AKT, ABL-25 BCR/MAPK, and DNA-Damage Response. A secondary screen verified many hits of the primary screen with antiviral activities at IC50 of below 25 nM. Drug validation for Berzosertib (in clinical trials for cancer treatment) in human cells showed it to be potent, safe and effective against SARS-CoV-2 in vitro. The underlying mechanism of Berzosertib as an ATR inhibitor in the DNA damage response pathway was investigated.
Impact for SARS-CoV2/COVID19 research efforts
Understand the virology and/or cell biology of SARS-CoV2/COVID19
Treat of SARS-CoV2/COVID19 positive individuals
In vitro study
Strengths and limitations of the paper
Novelty: Previously known small molecule kinase inhibitors but here identified to exhibit anti-SARS-COV-2 activity.
New understanding of the cellular signalling pathways involved in SARS-CoV-2 infection.
Standing in the field:The pathways that were most targeted by the antiviral compounds are known to be important for other viruses (e.g. Influenza, Herpesviruses..), which supports their importance for SARS-CoV-2.
Appropriate statistics: Students t-test to compare two groups; correct
Viral model used:SARS-CoV-2 (Isolate USA-WA1/2020)
Translatability:Eight clinical studies (Phase 1 and 2) showed limited side effects and good tolerance of Berzosertib and also other components of the screen are under current clinical evaluation. They are tested for cancer treatment, but could be repurposed as drug candidates for SARS-CoV-2 therapy. Further pre-clinical studies are being conducted with the aim for Investigational New Drug (IND) application for clinical trials in patients.
Main limitations: Only in vitro cell experiments. In vivo safety, toxicity and efficacy studies needed for clinical progress.
Mechanistic studies are minimal and not conclusive, further work needed to prove mode of action.