Over the past 16 months and against the backdrop of the COVID-19 health crisis, thousands of drugs have been tested with a view to repurpose them to tackle SARS-CoV-2. Many of these drugs have demonstrated potential antiviral activity (23 compounds including hydroxychloroquine, azithromycin, amiodarone and 4 others tested in clinical trials). Given this high number of potential treatments, the University of California San Francisco (UCSF), the Quantitative Biosciences Institute, the Institut Pasteur and Novartis joined forces as part of an international collaboration to demonstrate that in vitro antiviral activity was in fact induced by a mechanism common to all the compounds: phospholipidosis. This research has revealed the importance of systematically testing phospholipidosis as part of the repurposing process, with a view to honing criteria for selecting drugs put forward for clinical trials. The results of the research were published in Science on June 22, 2021.
Since the beginning of the SARS-CoV-2 outbreak, and in light of the emergency health situation, the international scientific community has sought to identify drugs already available on the market that could be repurposed to treat COVID-19.
Many of these have been identified as potentially having an antiviral effect on SARS-CoV-2 in vitro, which prompted scientists at the University of California San Francisco, the Quantitative Biosciences Institute, the Institut Pasteur and Novartis to verify their genuine efficacy for tackling this novel coronavirus. Through this international collaboration, they were able to demonstrate that the antiviral activity of certain molecules was in fact induced by phospholipidosis, an ancillary mechanism common to all the various compounds.
Phospholipidosis involves excessive accumulation of phospholipids in tissues and a change in the way phospholipids move in cells. This phenomenon is tolerated by humans in the short term and occurs to a limited extent when using most drugs. It is accepted since the drugs' therapeutic effect is greater than the side effects of phospholipidosis.
Marco Vignuzzi, Head of the Viral Populations and Pathogenesis Unit at the Institut Pasteur and joint last author of the study sheds light on the importance of this study and the impact of these results on future drug repurposing research.
Marco Vignuzzi, head of the Viral Populations and Pathogenesis Unit at the Institut Pasteur
We have now demonstrated through this research that it is worth considering systematically testing phospholipidosis in the in vitro stage.
Copyright : Stéphanie Beaucourt
What evidence led you to consider this research theory?
Since the beginning of the outbreak, a surprising number of drugs have been identified as having an antiviral effect in studies on compound repurposing conducted by our consortium. This number (over 20) seemed a little too encouraging from a scientific perspective. Studies conducted by other teams produced similar results for other drugs. However, all these drugs' structures were different, and there was nothing to suggest that they were effective due to a common mechanism. We therefore considered whether the observed effects may be caused by a common underlying mechanism unrelated to any genuine antiviral activity.
How did you analyze these results?
Most of these compounds are categorized as cationic amphiphilic drugs. Their physicochemical structure led us to examine the link between a phenomenon known as "phospholipidosis" and the antiviral activity observed. We demonstrated a direct correlation between the rate of phospholipidosis and the in vitro antiviral effect initially observed. This can be explained by the fact that SARS-CoV-2 is itself dependent on cellular lipids, and therefore phospholipidosis disrupts viral replication. Unfortunately, this mechanism cannot be used in connection with drugs that are effective in vivo, as this would mean administering treatments over long periods before they genuinely started to affect viral replication. This is not a viable option, since phospholipidosis is toxic for human cells in the long term. Therefore, most compounds that we tested have no genuine antiviral effect.
What do these results mean in a general sense for repurposed drugs? Is this specific to COVID-19?
Although they have been put forward for testing in clinical trials, most compounds repurposed to treat COVID-19 have no genuine antiviral effect. This is the first time that so many drugs have been tested for repurposing, as they represent a useful therapeutic tool in the event of a new outbreak. Several of them had already been identified as having an antiviral effect against other viruses (it is highly likely that this is linked to phospholipidosis). We have now demonstrated through this research that it is worth considering systematically testing phospholipidosis in the in vitro stage to avoid embarking on additional research on compounds that have this effect, which means that, in most cases, repurposing will not work for these drugs. However, it is still possible that some drugs may induce phospholipidosis while also having a genuine antiviral effect. This is yet to be determined.
Source
Drug-induced phospholipidosis confounds drug repurposing for SARS- CoV-2, Science, 22 juin 2021
Tia A. Tummino1,2,3,4†, Veronica V. Rezelj5†, Benoit Fischer6†, Audrey Fischer6†, Matthew J. O’Meara7, Blandine Monel8, Thomas Vallet5, Kris M. White9,10, Ziyang Zhang3,4,11,12, Assaf Alon13, Heiko Schadt6, Henry R. O’Donnell1, Jiankun Lyu1,3,4, Romel Rosales9,10, Briana L. McGovern9,10, Raveen Rathnasinghe9,10,14, Sonia Jangra9,10, Michael Schotsaert9,10, Jean-René Galarneau15, Nevan J. Krogan3,4,11,16, Laszlo Urban15, Kevan M. Shokat3,4,11,12, Andrew C. Kruse13, Adolfo García-Sastre9,10,17,18, Olivier Schwartz8, Francesca Moretti*6, Marco Vignuzzi5*, Francois Pognan6*, Brian K. Shoichet1,3,4*
1 Department of Pharmaceutical Chemistry, University of California San Francisco (UCSF), San Francisco, CA, USA.
2 Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, UCSF, San Francisco, CA, USA.
3 Quantitative Biosciences Institute (QBI), UCSF, San Francisco, CA, USA.
4 QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.
5 Institut Pasteur, Viral Populations and Pathogenesis Unit, CNRS UMR 3569, 75724 Paris, Cedex 15, France.
6 Novartis Institutes for BioMedical Research, Preclinical Safety, Basel, Switzerland.
7 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
8 Institut Pasteur, Virus and Immunity Unit, CNRS UMR 3569, 75724 Paris, Cedex 15, France.
9 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
10 Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11 Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, CA, USA.
12 Howard Hughes Medical Institute, UCSF, San Francisco, CA, USA.
13 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
14 Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15 Novartis Institutes for BioMedical Research, Preclinical Safety, Cambridge, MA, USA.
16 Gladstone Institute of Data Science and Biotechnology, J. David Gladstone Institutes, San Francisco, CA 94158, USA.
17 Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
18 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.