Ecxerpts from a recent scientific paper, bold mine.
This is pre-publication, are their any researchers on this board who could contact the author RE: blacamarsine?
ABSTRACT An 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 affinitypurification 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.
Identification of existing drugs targeting SARS-CoV-2 human host factors. To identify small molecules targeting human proteins in the SARS-CoV-2 interactome, we sought ligands known to interact with the human proteins, often directly but also by pathway and complexes, drawing on chemoinformatics databases and analyses (Methods). Molecules were prioritized by the quality statistical significance of the interaction of the human and viral proteins, by their status as approved drugs, investigational new drugs (INDs, “clinical” in Table 1a,b), or as preclinical candidates, by their apparent selectivity, and by their ready availability (for purchase availability notes, see Supplemental Tables 3 and 4) Chemoinformatics searches of the literature yielded 15 approved drugs, four investigational new drugs (clinical), and 18 pre-clinical candidates (Table 1a), while specialist knowledge revealed 12 approved drugs, 10 investigational new drugs (clinical), and 10 preclinical candidates (Table 1b). Of the 332 human targets that interact with the viral bait proteins with high significance, 62 have drugs/INDs/preclinical molecules that modulate them (Fig. 3). If we reduce our threshold slightly, we find an additional four human targets, revealing a total of 66 human targets (Supplementary Tables 3 and 4). The drug-human protein associations may be represented on its own, highlighting potentially exploitable interactions, and revealing new connections among the targets (Fig. 5a). There are several mechanistically interesting, and potentially disease-relevant drug-target interactions revealed in the chemoinformatic network (Fig. 5a, Extended Data Fig 9). Among them, the well-known chemical probe, Bafilomycin A1, is a potent inhibitor of the human prey protein, the V1-ATPase. Bafilomycin’s inhibition of this cotransporter acts to prevent the acidification of the lysosome, inhibiting autophagy but also cellular trafficking, which could be potentially relevant for the viral life-cycle. Similarly, several well-known epigenetic regulators were prominent among the human “prey” interactors, including HDAC2, BRD2 and BRD4, which interact with viral proteins nsp5 and E, respectively (Figs. 3 and 5a). The approved drug Valproic acid (an anticonvulsant) and the pre-clinical candidate Apicidin inhibit HDAC2 with affinities of 5 and 120 nM, respectively, while clinical compounds like ABBV-744 and CPI-0610 act on the two bromodomains, with affinities of 2 and 39 nM, respectively, as do several preclinical compounds (Table 1a,b). As a final example, we were intrigued to observe that the SARS-CoV-2 Nsp6 protein interacts with the Sigma receptor, which is thought to participate in ER stress response70. Similarly, the Sigma2 receptor interacted with the vial protein orf9. Both Sigma1 and Sigma2 are promiscuous receptors that interact with many non-polar, cationic drugs. We prioritized several of these drugs based on potency or potential disease relevance, including the antipsychotic Haloperidol, which binds in the low nM range to both receptors, and Chloroquine, which is currently in clinical trials for COVID-19 and has mid-nM activity vs the Sigma1 receptor, and low uM activity against the Sigma2 receptor. Because many patients are already treated with drugs that have the Sigma receptors as off-targets, associating clinical outcomes with treatment with these drugs may merit investigation, a point to which we return. Finally, In addition to the druggable host factors, a few of which we have highlighted here, the viral-human interactome reveals many traditionally “undruggable” targets. Among these, for instance, are components of the centriole such as CEP250, which interacts with the viral Nsp13. Intriguingly, a very recent patent disclosure revealed a natural product, WDB002, that directly and specifically targets CEP250. As a natural product, WDB002 would likely be harder to source than the molecules on which we have focused on here, but may well merit investigation. Similarly, other “undruggable” targets may be revealed to have compounds that could usefully perturb the viral-human interaction network, and act as leads to therapeutics.
Beyond direct interactions, several drug-pathway interactions seemed noteworthy. The human purine biosynthesis enzyme Inosine-5'-monophosphate dehydrogenase (IMPDH2) interacts with the viral protein nsp14. Several chemically diverse compounds inhibit IMPDH2, including the pre-clinical mycophenolic acid (20 nM), the approved antiviral drug ribavirin (200 nM), and the investigational new drug Merimepodib (10 nM) (Table 1a). Intriguingly, the preclinical molecule Sanglifehrin A (Table 1b) is known to act as a molecular glue linking IMPDH with cyclophilin A (Fig. 5b), which itself is implicated in viral capsid packaging, even though it itself is not a human “prey” in the viral-human protein interactome. Similarly, direct viral-human interactions with proteins regulated by the mTORC1 pathway, such as LARP1, and FKBP7, which interact with the viral N and Orf8 proteins, led us to inhibitors of mTORC1, even though that kinase itself is not found to directly interact with a viral protein (Fig. 5c). Thus, sapanisertib and rapamycin are low nM inhibitors of mTORC1, while metformin is an indirect modulator of this protein complex. To identify small molecules targeting human proteins in the SARS-CoV-2 interactome, we sought ligands known to interact with the human proteins, often directly but also by pathway and complexes, drawing on chemoinformatics databases and analyses (Methods). Molecules were prioritized by the quality statistical significance of the interaction of the human and viral proteins, by their status as approved drugs, investigational new drugs (“clinical” in Table 1a,b), or as preclinical candidates, by their apparent selectivity, and by their ready availability. Chemoinformatics searches of the literature yielded 15 approved drugs, four investigational new drugs (clinical), and 18 pre-clinical candidates (Table 1a, Supplementary Table 3), while specialist knowledge revealed 12 approved drugs, 10 investigational new drugs (clinical), and 10 pre-clinical candidates (Table 1b, Supplementary Table 4). Of the 332 human targets that interact with the viral bait proteins with high significance, 62 have drugs/clinical/preclinical molecules that modulate them (Fig. 3). If we relax our threshold slightly, we reveal 66 human targets (Supplementary Tables 3 and 4). The drug-human protein associations may be represented on its own, highlighting potentially exploitable interactions, and revealing new connections among the targets (Fig. 5a).
Download the paper at the link below and look at the table titled:
Table 1a. Literature-deriveda drugs and reagents that modulate SARS-Cov-2 interactors.
