A host-directed intervention can be a useful stop gap before vaccine distribution. The Nature article by Gordon et al. is impressive for its scale and velocity. It represents an early attempt to identify possible COVID-19 treatments in the existing pharmacologic armamentarium and underscores that medium- and high-throughput assays are necessary to quickly test compounds that may be useful in the battle against this raging pandemic.
A total of 69 compounds were initially identified. Of these, 48 and an additional 18 (n=66) were tested for antiviral activity. It is not surprising that protein biogenesis inhibitors (zotatifin, ternatin-4, and PS3061) exerted antiviral effects, given that viruses are dependent on host machinery for their replication and propagation. They are also effective at concentrations of 10-100 nM, making them attractive candidates for human use.
The role of Sigma receptors is somewhat muddier. These non-opioid receptors bind several classes of psychotropic drugs, but their molecular mechanisms are unclear. It has been argued that they are not traditional receptors; rather, they are unique integral membrane chaperones or scaffolding protein that can be pharmacologically regulated. Gordon and colleagues hypothesized that they may decrease infectivity by perturbing the cell stress response. A review by Su et al. stated that stimulation of Sigma 1 by agonists or stressors induces it to translocate to the cell membrane where it interacts with ion channels, receptors, and kinases. Two of the tested drugs (clemastine and cloperastine) are approved antitussives and antihistamines and have been used for decades. Still, the study authors note that it is unclear if their pharmacokinetics are suitable for antiviral use as they also bind to side-effect targets. This is also the issue with HCQ, which increases the risk of cardiac arrhythmia. Indeed, on June 15, 2020, the U.S. FDA revoked its emergency use authorization for HCQ, stating that the “known and potential benefits…no longer outweigh the known and potential risks for authorized use.” Clearly, much more work is needed to untangle the role of Sigma receptors in SARS-CoV-2 infection.
There is one major limitation of this study that should be addressed in future work. Although HEK293T/17 cells are infected by SARS-CoV-2, the primary site of infection is the lung. Establishing assays in a more relevant cell line are needed before moving promising compounds to animal trials.
Still, the rapidity of this work (prepublished just 4 months after the first outbreak) demonstrates the utility of this experimental pipeline for drug discovery to test pan-viral strategies. It is possible that host factor-targeting agents could be used in combination with other drugs that inhibit viral enzymes. Medium- to high-throughput screening will hopefully hasten the development of effective antivirals and combination therapies for SARS-CoV-2/COVID-19.
Gordon DE, Jang GM, Bouhaddou M, et al. A SARS CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020 [prepublication]. doi: 10.1038/s41586-020-2286-9
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