A proteomics approach to identify novel therapeutic targets against Covid-19.

In spite of the overall mitigation of the measures adopted to contain the diffusion, Covid-19 disease still represents an health emergency, and effective treatments are urgently needed.

Main findings. In a recent paper published in Nature, by using a proteomic approach scientists have generated a proteomic profile of SARS-CoV2 infected cells, thus identifying critical pathways of the human host cell required for virus replication, which were majorly affected by viral infection and whose targeting by known drugs, at clinically useful concentrations –some of them FDA approved or in clinical trial– has proven efficacious in halting virus replication.

Experimental details. The authors firstly generated a cell system to model the disease, by exploiting a colon carcinoma cell line. Previous studies have indeed shown the expression of ACE2 receptor –required for virus binding and human cell infection– in cells of the gastrointestinal tract as well as in lung cells, likely responsible for virus infection and amplification and the observed gastrointestinal symptoms of Covid-19 patients. In this cell model system, the pathogenic effect of the virus was visible as soon as 24 hours after infection. 

Analyses of protein levels before and after infection highlighted extensive changes occurring 24 hours post infection. Major changes were observed mainly in two main groups of proteins: those involved in cholesterol metabolism and those linked to RNA processing, such as splicesome and carbon metabolism. Drug inhibition, at non-toxic concentrations, of either splicing or glycolysis (carbon metabolism, by using 2-DG) prevented virus replication, proposing these pathways as potential therapeutic targets for Covid-19.

Furthermore, by analysing cellular proteins whose increase over time mirrored the increase of viral proteins (thus potentially playing a role in viral replication) the authors identified critical components of the nucleic acid metabolism pathways. Indeed, coronaviruses need nucleotides of the host cell to replicate. Drugs interfering with nucleotide metabolism, such as Ribavirin, which has been used in the past to inhibit viral replication of SARS-CoV with significant effect, inhibited SARS-CoV2 replication at clinically relevant concentrations.

Finally, increased levels of components of the protein homeostasis machinery were observed, consistent with a perturbed homeostasis due to the stress caused by the folding of viral proteins. Specific inhibitors of protein homeostasis mechanisms, previously used to treat influenza virus A and B, inhibited SARS-CoV2 replication.

Conclusions. This work unveiled critical cellular pathways modulated upon SARS-CoV2 infection, required for the replication of the virus itself, providing solid experimental data for therapeutic interventions. Importantly, a clinical trial to test Ribavirin (interfering with nucleic acid metabolism) efficacy against Covid-19 has been recently started (https://clinicaltrials.gov/ct2/show/NCT04356677 ).