The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratorydisease, has infected over 2.3 million people, killed over 160,000, and causedworldwide social and economic disruption.
There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection.
To address this, were cloned, tagged and expressed 26 of the 29 SARS-CoV-2
proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs).
Among these, were identified 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds).
Screening a subset of these in multiple viral assays were identified two sets
of pharmacological agents that displayed antiviral activity:
- inhibitors of mRNA translation and
2. predicted regulators of the Sigma1 and Sigma2 receptors.
Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
Within these sets are at least five targets and over ten different chemotypes, suggesting a rich landscape for optimization.
The chemo-proteomic analysis that emerges from this study not only
highlights clinically actionable drugs that target human proteins in the interactome, it provides a context for interpreting their mechanism of
The potent efficacy of the translation inhibitors on viral infectivity—in the 10 to 100 nM range—makes these molecules attractive as candidate antivirals, and also highlights this pathway as a point of intervention.
While the mechanism of action of the drugs targeting the Sigma1 and Sigma2 receptors remains less defined, their activity as both anti- and pro-viral agents is mechanistically suggestive.
The relatively strong efficacy of PB28, at 280 nM IC90 in the viral titer assay, and its high selectivity against off-targets, suggests that molecules of this class may be optimized towards therapeutics.
Whereas it is unclear that approved drugs like clemastine and cloperastine, which are used as antihistamines and antitussives, have pharmacokinetics suitable for antiviral therapy, nor are they free of binding to side-effect targets, they have been used for decades. We do caution against their use outside of controlled studies, due to their side-effect liabilities.
By the same standard, we find that the widely used antitussive dextromethorphan harbors proviral activity and therefore its use
should merit caution and further study in the context of COVID-19.
More positively, there are dozens of approved drugs that are active against Sigma receptors that remain untested, some of which, intriguingly, have begun to appear in other studies, although not recognized as Sigma ligands. Therefore, this area of pharmacology has great promise for repurposing and for the optimization of new agents in the fight against COVID-19.
Our approach of host-directed intervention as an antiviral strategy
overcomes problems associated with drug resistance and may also
provide pan-viral therapies as we prepare for the next pandemic.
Furthermore, the possibilities for co-therapies are expanded, for
example with drugs directly targeting the virus, including remdesivir,
and, as we demonstrate in this study, a rich set of repurposing opportunities are illuminated.
More broadly, the pipeline described here represents a new approach for drug discovery not only for pan-viral strategies, but for many diseases, and illustrates the speed in which science can be moved forward using a multi-disciplinary and collaborative approach.