Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection

There is a critical need for safe and effective drugs for COVID‐19. Only remdesivir has received authorization for COVID‐19 and has been shown to improve outcomes but not decrease mortality. However, the dose of remdesivir is limited by hepatic and kidney toxicity. ACE2 is the critical cell surface...

Full description

Saved in:
Bibliographic Details
Published in:EMBO molecular medicine Vol. 13; no. 1; pp. e13426 - n/a
Main Authors: Monteil, Vanessa, Dyczynski, Matheus, Lauschke, Volker M, Kwon, Hyesoo, Wirnsberger, Gerald, Youhanna, Sonia, Zhang, Haibo, Slutsky, Arthur S, Hurtado del Pozo, Carmen, Horn, Moritz, Montserrat, Nuria, Penninger, Josef M, Mirazimi, Ali
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 11.01.2021
EMBO Press
John Wiley and Sons Inc
Springer Nature
Subjects:
ACE2
Adenosine Monophosphate - analogs & derivatives
Adenosine Monophosphate - pharmacology
Adenylate kinase
Alanine - analogs & derivatives
Alanine - pharmacology
Angiotensin-converting enzyme 2
Angiotensin-Converting Enzyme 2 - pharmacology
Animals
Antiviral Agents - pharmacology
Antiviral drugs
Cell surface
Cells, Cultured
Chlorocebus aethiops
clinical trial
Clinical trials
Cloning
combination therapy
Coronaviruses
COVID-19
COVID-19 Drug Treatment
Cytotoxicity
Disease transmission
Drug dosages
Drug Synergism
EMBO23
Enzymes
FDA approval
HIV
Homeostasis
Human immunodeficiency virus
Humans
Infections
Kidneys
Life cycles
Liver
Models, Molecular
Mortality
Mutagenesis
Mutation
Organoids
Patients
Recombinant Proteins - pharmacology
Ribonucleic acid
RNA
RNA polymerase
SARS-CoV-2 - drug effects
SARS-CoV-2 - physiology
Severe acute respiratory syndrome coronavirus 2
Spheroids
Toxicity
treatment
Vero Cells
Virus Internalization - drug effects
Virus Replication - drug effects
Viruses
clinical trial
treatment
combination therapy
COVID‐19
COVID-19
ISSN:1757-4676, 1757-4684, 1757-4684
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:There is a critical need for safe and effective drugs for COVID‐19. Only remdesivir has received authorization for COVID‐19 and has been shown to improve outcomes but not decrease mortality. However, the dose of remdesivir is limited by hepatic and kidney toxicity. ACE2 is the critical cell surface receptor for SARS‐CoV‐2. Here, we investigated additive effect of combination therapy using remdesivir with recombinant soluble ACE2 (high/low dose) on Vero E6 and kidney organoids, targeting two different modalities of SARS‐CoV‐2 life cycle: cell entry via its receptor ACE2 and intracellular viral RNA replication. This combination treatment markedly improved their therapeutic windows against SARS‐CoV‐2 in both models. By using single amino‐acid resolution screening in haploid ES cells, we report a singular critical pathway required for remdesivir toxicity, namely, Adenylate Kinase 2. The data provided here demonstrate that combining two therapeutic modalities with different targets, common strategy in HIV treatment, exhibit strong additive effects at sub‐toxic concentrations. Our data lay the groundwork for the study of combinatorial regimens in future COVID‐19 clinical trials. Synopsis A human kidney organoid model was used to test antiviral drugs against SARS‐CoV‐2 infections, highlighting the efficiency of combining two different approaches to reduce SARS‐CoV‐2 viral load. Our findings open a promising way for clinical trials using safer and more efficient combination therapies in COVID‐19. Ak2 is central to the remdesivir cytotoxicity pathway. Combination of drugs targeting different steps of SARS‐CoV‐2 infection has an additive antiviral effect. Development of a safer and more effective anti‐SARS‐CoV‐2 therapies. Graphical Abstract A human kidney organoid model was used to test antiviral drugs against SARS‐CoV‐2 infections, highlighting the efficiency of combining two different approaches to reduce SARS‐CoV‐2 viral load. Our findings open a promising way for clinical trials using safer and more efficient combination therapies in COVID‐19.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:1757-4676
1757-4684
1757-4684
DOI:10.15252/emmm.202013426