Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection. Issue 1 (14th December 2020)

• Record Type: Journal Article
• 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
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-14
• Subjects: clinical trial -- combination therapy -- COVID‐19 -- treatment; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202013426
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: 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. 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.