Abstract
Protein–protein interactions (PPIs) are the vital engine of cellular machinery. After virus entry in host cells the global organization of the viral life cycle is strongly regulated by the formation of virus-host protein interactions. With the advent of high-throughput -omics platforms, the mirage to obtain a “high resolution” view of virus–host interactions has come true. In fact, the rapidly expanding approaches of mass spectrometry (MS)-based proteomics in the study of PPIs provide efficient tools to identify a significant number of potential drug targets. Generation of PPIs maps by affinity purification-MS and by the more recent proximity labeling-MS may help to uncover cellular processes hijacked and/or altered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing promising therapeutic targets. The possibility to further validate putative key targets from high-confidence interactions between viral bait and host protein through follow-up MS-based multi-omics experiments offers an unprecedented opportunity in the drug discovery pipeline. In particular, drug repurposing, making use of already existing approved drugs directly targeting these identified and validated host interactors, might shorten the time and reduce the costs in comparison to the traditional drug discovery process. This route might be promising for finding effective antiviral therapeutic options providing a turning point in the fight against the coronavirus disease-2019 (COVID-19) outbreak.
Highlights
The global health emergency for the current worldwide outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since December 2019, has posed the urgent requirement to discover specific treatments to stop the pandemic.international efforts from scientific community have provided an extraordinary wealth of studies which have greatly contributed to better elucidate the mechanism of pathogenicity of SARS-CoV-2 [1]
AP, bound proteins (i.e., proteins not recovered in the control cific antibody or a specific ligand bound to a solid support experiment) are digested and identified by liquid chromatography (LC)-mass spectrometry (MS)/MS (Figure 1). One limitation of this approach may be due to the formation during cell lysis of nonspecific interactions, which may sometimes include in the complex non-physiological targets. This tool is not properly suitable for the detection of protein complexes in which a weak affinity interaction is established between the interactors and/or for complexes characterized by fast kinetic of dissociation, for example transient interactions occurring in post translational modifications (PTMs) or those occurring at poorly soluble membranes proximity
(a) the observation that sigma-1 was found to be an interactor of SARS-CoV-2 Nsp6 in all the reports which searched for preys of this viral protein; (b) the evidence that sigma-1 proved to be a proviral dependency factor in both assays used by Gordon and colleagues; (c) the significant size of the clinical sample make these results very interesting and an even nicer example of mechanism-based drug discovery
Summary
The global health emergency for the current worldwide outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus since December 2019, has posed the urgent requirement to discover specific treatments to stop the pandemic. The large datasets of PPIs generated by these approaches may reveal new host-virus interactions targetable by host-directed therapies on the basis of already existing small-molecule candidates. Maps of PPIs between SARS-CoV-2 proteins and human proteins have been very recently identified (determined/uncovered) by both AP-MS [17,18,19,20,21] and BioID approaches [22,23,24]. The intriguing and fascinating SARS-CoV-2 landscapes emerging from these studies offer an extraordinary springboard for the systematic exploration of the virus–host interface in the search of host proteins already targeted by existing drugs. We furnish an in-depth analysis of the published datasets and conclude this paper with perspectives towards future follow-up experiments and further investigations which might provide a valid support for the rapid development of host-directed anti-SARS-CoV-2 therapeutics
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