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 disruption 1,2 . 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.

ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 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 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

16‐Ferrocenylmethyl‐estra‐1,3,5(10)‐triene‐3,17β‐diol crystallizes in a triclinic unit cell and P1 space group. It contains four crystallographic independent molecules in the unit, representing four different conformers of the ferrocene–hormone conjugate. It provides evidence of a low rotational barrier around C19–C20 and the existence of alpha and beta conformers. The four conformers are interconnected by hydrogen bonds through hydroxyl groups of rings A and D. Density functional theory studies show the rotational barrier energy to be 4.96 Kcal/mol and the preferred conformer has a dihedral angle φ2 (defined as C16–C19–C20–C21) of 85.79°. This angle represents the conformer with the lowest steric strains. Docking studies between the subject compound and human serum albumin (HSA) showed that the most likely binding pocket of HSA is drug‐binding site 2. Quenching fluorescence spectroscopy was used to study HSA–ferrocene conjugate interaction and results showed that the complex formation was static and dominated by van der Waals and electrostatic/hydrogen bonding interactions.

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