Here’s a new paper (open access) from a large multi-center team of authors urging caution on many of the reports of small-molecule repurposing screens against coronavirus activity. The list of drugs that has shown activity in vitro is long, and the list of potential targets is as well. But when you look at those targets, it’s hard to untangle things – for example, many compounds that are nanomolar ligands at sigma receptors have shown activity, but other nanomolar ligands are inactive. (To be sure, there are an awful lot of sigma receptor ligands out there, and if that had turned out to be an antiviral target, it would be the first solid use for sigma that I could recall). The same situation holds for the other proposed targets; there’s a lot of conflicting and contradictory evidence.
The new paper makes a strong case that there is an underlying mechanism, though: membrane disruption through phospholipidosis. Small molecules that have a charged cationic group and another region that’s very lipophilic tend to cause this problem at higher concentrations. Such molecules seem to disrupt lipid degradation and recycling when they accumulate in cellular compartments like endosomes and lysosomes, and the effects can be seen in those structures and other cell membranes as excess phospholipids accumulate.
As the authors point out, these pathways are also essential for viral infection, so this sort of trouble would show up as an antiviral effect in cell assays. The coronavirus (and many others) depends on hijacking membrane handling inside the cell in order to replicate, so affecting phospholipid pathways can throw that off. But it’s not something that you can translated to a real therapeutic effect, of course. For one thing, you need high concentrations of the drugs. These can be reached in cell assays, but it’s not as easy to do that in vivo. And more importantly, phospholipidosis is a bad thing in itself, and is not the sort of effect you want to enlist to fight off viral infections. This is something that everyone is going to have to keep in mind for the future:
This apparently general mechanism may be responsible for many of the drug repurposing hits for SARS-CoV-2, and an extraordinary amount of effort and resources lavished on drug discovery against this disease. We explore the prevalence of this confound in SARS-CoV-2 repurposing studies, how phospholipidosis correlates with inhibition of viral infection, and how to eliminate such hits rapidly so as to focus on drugs with genuine potential against COVID-19, and against new pandemics yet to arise.
The paper shows a strong correlation between the induction of phospholipidosis and in vitro antiviral activity across a large set of compounds. It’s interesting to note that the list of molecules that induce this effect includes hydroxychloroquine and azithromycin, and the paper hypothesizes that this is indeed the source of their activity in cellular assays of viral infection. But the most potent compounds still could not translate to in vivo efficacy in rodent models, likely for just the reason mentioned above. It’s an artifact, a false positive, and people should be aware of it and stop chasing it. It’s costing us:
The cost to the community of investments in what appears to be a confound merits consideration for future pandemics. According to the DrugBank COVID-19 dashboard (49), which draws from U.S. and international clinical trials, putatively antiviral CADs have been promoted into an astonishing 316 Phase I to Phase III clinical trials against COVID-19. While 57% of these study the phospholipidosis-inducing CADs hydroxychloroquine (Fig. 3A, top row) or chloroquine, that still leaves 136 trials across 33 other predicted or known phospholipidosis-inducers. Using conservative estimates (50, 51), the expense of the clinical trials component alone, over the last year, for phospholipidosis-inducing CADs may be over $6 billion US dollars (table S9).
That could have been put to better use, clearly. One of the things that I very much hope that we get out of this pandemic experience is the realization that our biomedical research infrastructure was in many ways not ready for this and did not always react well. The vaccine development story has been a very positive one, fortunately, but if we run into a pathogen that is harder to vaccinate against – and there are plenty of them – then we will be thrown back on small-molecule approaches, among others. In which case we had better not spend billions of dollars on scores of useless clinical trials with molecules that have no chance of actually working. Right?
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