Similar to the clinical success with HIV remission, combination drug therapies – so-called “drug cocktails” – are entering the clinical pipeline for SARS-CoV-2.

At least 10 different drug compounds ranging from cancer therapies to antipsychotics and antihistamines may be effective at preventing the new coronavirus from multiplying in the body, according to a multidisciplinary study conducted by a team of scientists in the United States and France. The researchers mapped the human proteins the virus interacts with inside the body when it infects cells and makes copies of itself, then looked for compounds that could block the virus from using those proteins. The result showed that 47 compounds in cell cultures had the desired effect, at least 10 of which are already in approved drugs or being studied for diverse conditions, but could be repurposed against COVID-19, the illness caused by the new coronavirus. Researchers have been rushing to develop experimental therapies as well as to repurpose existing drugs to treat patients with COVID-19 and communities are pinning high hopes on Gilead Sciences Inc’s experimental antiviral drug, remdesivir. In the new study, published in the journal Nature on Thursday, candidates for repurposing included allergy medicine ingredients including clemastine, the antipsychotic haloperidol, and malaria drug hydroxychloroquine. The study also revealed why hydroxychloroquine is often found to have toxic effects on the heart. The malaria drug, which has been repeatedly touted by U.S. President Donald Trump, binds to a receptor on human cells, which the virus needs to infect the cell. But hydroxychloroquine also hits a particular protein in the heart tissue, which could explain the drug’s effect on heart rhythms – a side effect recently flagged by U.S. and EU health regulators. The team also found that an experimental chemical, PB28, was 20-times more potent than hydroxychloroquine in targeting the receptor, but had far less affinity for the heart protein. The hormone progesterone was also found to act against the virus, which might shed some light on the reasons that men appear to be more susceptible to COVID-19 and more often suffer severe complications. Another compound found to have antiviral activity was plitidepsin, used in Madrid-based PharmaMar’s experimental cancer therapy Aplidin that is currently being tested in COVID-19 trials in Spain. “Some of our drugs and compounds are many times more potent than remdesivir, at least in a laboratory setting,” study author Nevan Krogan of the University of California San Francisco, said in a media briefing. Gilead’s remdesivir could be the closest to regulatory approval after initial trial results on Wednesday found that the drug helped patients recover more quickly. The team said it would continue testing the candidates they have identified and use the same methods to further study the biology of the disease for more insights. – Source: France24

A SARS-CoV-2 protein interaction map reveals targets for drug repurposingDownload PDF

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Abstract

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. 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, we 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, we identify 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 identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and 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.

Author information

Correspondence to Marco Vignuzzi or Adolfo García-Sastre or Kevan M. Shokat or Brian K. Shoichet or Nevan J. Krogan.

Supplementary information

Supplementary Information

This file contains supplemental discussion, supplemental methods, and corresponding supplemental references. The supplemental discussion is a comprehensive literature review of all 27 wild-type and mutant SARS-CoV-2 bait protein-protein interaction (PPI) subnetworks. Individual bait subnetwork images are provided at the front of the document for reference (and are zoomed view representations from Figure 3 of the main text). Supplemental methods that were used to generate the data in supplemental tables and extended data figures (when not referenced in the main text) are provided after the supplemental discussion. Supplemental references corresponding to the supplemental discussion and methods are provided at the end of the document.

Reporting Summary

Peer Review File

Supplementary Figure 1

Raw Western blot images with molecular weight ladder and black box outlining the image cropping used to generate Extended Data Figure 1b.  Both blots were probed with primary antibody α-streptavidin, Qiagen #34850 (1:2500); and secondary α-mouse-HRP conjugate, BioRad #1706516 (1:20,000).

Supplementary Table 1

Scoring results for all baits and all proteins, showing spectral counts of experimental samples (columns AvgSpec and Spec) and empty controls (column Ctrl Counts).

Supplementary Table 2

SARS-CoV-2 high confidence interactors, showing spectral counts of experimental samples (columns AvgSpec and Spec) and empty controls (column Ctrl Counts).

Supplementary Table 3

PAML results for the 332 genes analyzed, sorted in order of statistical significance. We used a likelihood ratio test to obtain a p-value, by comparing twice the difference in log-likelihoods with the chi-squared distribution with 1 degree of freedom. After running all 332 analyses, we used the Benjamini-Hochberg procedure to control the false-discovery rate.

Supplementary Table 4

Literature-derived drugs and reagents that modulate SARS-CoV-2 interactors. Drug-target associations drawn from chemoinformatic searches of the literature, including information about purchasability.

Supplementary Table 5

Expert-identified drugs and reagents that modulate SARS-CoV-2 interactors. Drug-target associations drawn from expert knowledge of human protein interactors of SARS-CoV-2 and reagents and drugs that modulate them; not readily available from the chemoinformatically-searchable literature

Supplementary Table 6

Summary of experimental results for drug SARS-CoV-2 viral inhibition.

Supplementary Table 7

Raw chemical associations to prey proteins IUPHAR/BPS Guide to Pharmacology (2020-3-12).

Supplementary Table 8

Raw chemical associations to prey proteins ChEMBL25.

Supplementary Data

This zipped folder contains genome annotation of SARS-CoV-2 USA-WA1 (genbank format), and plasmid maps for all constructs generated for this study (genbank format).