Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2-Reference-Cited by-同舟云学术

Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2

Published:2021-07-30 Issue:6554 Volume:373 Page:541-547
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Tummino Tia A.¹²³⁴^ORCID,Rezelj Veronica V.⁵^ORCID,Fischer Benoit⁶^ORCID,Fischer Audrey⁶^ORCID,O’Meara Matthew J.⁷^ORCID,Monel Blandine⁸^ORCID,Vallet Thomas⁵^ORCID,White Kris M.⁹¹⁰^ORCID,Zhang Ziyang³⁴¹¹¹²^ORCID,Alon Assaf¹³^ORCID,Schadt Heiko⁶^ORCID,O’Donnell Henry R.¹^ORCID,Lyu Jiankun¹³⁴^ORCID,Rosales Romel⁹¹⁰^ORCID,McGovern Briana L.⁹¹⁰,Rathnasinghe Raveen⁹¹⁰¹⁴^ORCID,Jangra Sonia⁹¹⁰,Schotsaert Michael⁹¹⁰^ORCID,Galarneau Jean-René¹⁵,Krogan Nevan J.³⁴¹¹¹⁶^ORCID,Urban Laszlo¹⁵^ORCID,Shokat Kevan M.³⁴¹¹¹²^ORCID,Kruse Andrew C.¹³^ORCID,García-Sastre Adolfo⁹¹⁰¹⁷¹⁸^ORCID,Schwartz Olivier⁸^ORCID,Moretti Francesca⁶^ORCID,Vignuzzi Marco⁵^ORCID,Pognan Francois⁶^ORCID,Shoichet Brian K.¹³⁴^ORCID

Affiliation:

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, 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.

Abstract

Screening for drugs that don’t work In the battle against COVID-19, drugs discovered in repurposing screens are of particular interest because these could be rapidly implemented as treatments. However, Tummino et al . deliver a cautionary tale, finding that many leads from such screens have an antiviral effect in cells through phospholipidosis, a phospholipid storage disorder that can be induced by cationic amphiphilic drugs (see the Perspective by Edwards and Hartung). There is a strong correlation between drug-induced phospholipidosis and inhibition of severe acute respiratory syndrome coronavirus 2 replication in cells. Unfortunately, drugs that have an antiviral effect in cells through phospholipidosis are unlikely to be effective in vivo. Screening out such drugs may allow a focus on drugs with better clinical potential. —VV

Funder

National Institutes of Health

Howard Hughes Medical Institute

National Institute of General Medical Sciences

Defense Advanced Research Projects Agency

Damon Runyon Cancer Research Foundation

National Institute of Allergy and Infectious Diseases

ASCRS Research Foundation

George Mason University

GlaxoSmithKline foundation

Open Philanthropy Project

Labex IBEID