ProteoCoV - Proteostasis as a target for antiviral therapies against SARS-CoV-2 - Characterization of proteostasis-specific inhibitors against SARS-CoV-2.

Therapeutic approaches against SARS-CoV-2 currently focus on repurposing of clinically approved drugs. Functional details on how these drugs affect SARS-CoV-2 are often unknown putting patient safety and clinical trials at risk. Our previous study on MERS-CoV revealed that autophagy, a mechanism for non-selective lysosomal protein degradation, is blocked by MERS-CoV infection. We now confirmed that SARS-CoV-2 also limits autophagy. Targeted induction of autophagy by clinically approved drugs reduced MERS-CoV and SARS-CoV-2 replication. Our preliminary data suggest that SARS-CoV-2 promotes selected degradation of proteins by activation of the ubiquitin proteasome system (UPS). We propose that SARS-CoV-2 modulates proteostasis by inhibiting non-selective autophagy while promoting selective proteasomal degradation. In the proposed project, we will perform pulsed-SILAC to analyze details of protein degradation processes upon SARS-CoV-2 infection on a proteome-wide scale. Identification, characterization and validation of candidate proteins and respective protein-targeting drugs will be done by established in silico, molecular and protein-biochemical techniques in combination with virological methods. Identified, clinically approved drugs will be tested by implemented in vitro methods to determine SARS-CoV-2 growth inhibition in non-toxic, nanomolar concentrations possibly encouraging clinical trials. The mechanistic insights into the virus host interplay will reveal novel, hypothesis-driven treatment and drug repurposing strategies against SARS-CoV-2.