Phospholipidosis is a shared mechanism underlying the in vitro antiviral activity of many repurposed drugs against SARS-CoV-2
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
Repurposing drugs as treatments for COVID-19 has drawn much attention. A common strategy has been to screen for established drugs, typically developed for other indications, that are antiviral in cells or organisms. Intriguingly, most of the drugs that have emerged from these campaigns, though diverse in structure, share a common physical property: cationic amphiphilicity. Provoked by the similarity of these repurposed drugs to those inducing phospholipidosis, a well-known drug side effect, we investigated phospholipidosis as a mechanism for antiviral activity. We tested 23 cationic amphiphilic drugs—including those from phenotypic screens and others that we ourselves had found—for induction of phospholipidosis in cell culture. We found that most of the repurposed drugs, which included hydroxychloroquine, azithromycin, amiodarone, and four others that have already progressed to clinical trials, induced phospholipidosis in the same concentration range as their antiviral activity; indeed, there was a strong monotonic correlation between antiviral efficacy and the magnitude of the phospholipidosis. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the gross physical properties of drugs, and does not reflect specific target-based activities, rather it may be considered a confound in early drug discovery. Understanding its role in infection, and detecting its effects rapidly, will allow the community to better distinguish between drugs and lead compounds that more directly impact COVID-19 from the large proportion of molecules that manifest this confounding effect, saving much time, effort and cost.
One Sentence Summary
Drug-induced phospholipidosis is a single mechanism that may explain the in vitro efficacy of a wide-variety of therapeutics repurposed for COVID-19.
Article activity feed
-
SciScore for 10.1101/2021.03.23.436648: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Certain caveats merit airing. First, the correlation we observe between antiviral activity and phospholipidosis, as strong as it is, does not illuminate the mechanism by which phospholipidosis is itself antiviral. …
SciScore for 10.1101/2021.03.23.436648: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Certain caveats merit airing. First, the correlation we observe between antiviral activity and phospholipidosis, as strong as it is, does not illuminate the mechanism by which phospholipidosis is itself antiviral. Phospholipidosis itself is only partly understood mechanistically, and there are no known genetic or chemical ways to inhibit drug-induced phospholipidosis, nor are there reliable target-selective reagents to induce it. Second, there is no consistent standard in the field as to the physical properties that will predict whether a molecule will induce phospholipidosis, and there are even non-CAD molecules that induce it (e.g., azithromycin). Thus, we have chosen conservative criteria to predict phospholipidosis-inducing CADs; while we believe that these will have relatively few false positive predictions, many phospholipidosis-inducing drugs may be missed. Third, phospholipidosis is a confound that only affects drugs repurposed for direct antiviral activity—it is irrelevant for drugs like dexamethasone (62) and for the CAD fluvoxamine (63) which have been repurposed for immunomodulatory treatment of COVID-19, nor is it relevant for antiviral CADs whose activity against the virus is well-below the range where phospholipidosis occurs. Fourth, our estimates of the clinical trial costs of CAD advancement for COVID-19 are clearly rough. If we have inadvertently included CADs advanced for immunomodulatory treatment, for instance, they will be too high. This would be balance...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
