Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection
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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202013426 |
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| author | Vanessa Monteil Matheus Dyczynski Volker M Lauschke Hyesoo Kwon Gerald Wirnsberger Sonia Youhanna Haibo Zhang Arthur S Slutsky Carmen Hurtado del Pozo Moritz Horn Nuria Montserrat Josef M Penninger Ali Mirazimi |
| author_facet | Vanessa Monteil Matheus Dyczynski Volker M Lauschke Hyesoo Kwon Gerald Wirnsberger Sonia Youhanna Haibo Zhang Arthur S Slutsky Carmen Hurtado del Pozo Moritz Horn Nuria Montserrat Josef M Penninger Ali Mirazimi |
| author_sort | Vanessa Monteil |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-07998970104b4c38b5f25f0f58d1b221 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-07998970104b4c38b5f25f0f58d1b2212025-08-20T03:43:29ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-12-011311810.15252/emmm.202013426Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infectionVanessa Monteil0Matheus Dyczynski1Volker M Lauschke2Hyesoo Kwon3Gerald Wirnsberger4Sonia Youhanna5Haibo Zhang6Arthur S Slutsky7Carmen Hurtado del Pozo8Moritz Horn9Nuria Montserrat10Josef M Penninger11Ali Mirazimi12Department of Laboratory Medicine, Unit of Clinical Microbiology, Karolinska InstituteAcus Laboratories GmbHDepartment of Physiology and Pharmacology, Karolinska InstituteNational Veterinary InstituteAPEIRON Biologics AGDepartment of Physiology and Pharmacology, Karolinska InstituteKeenan Research Centre for Biomedical Science at Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of TorontoKeenan Research Centre for Biomedical Science at Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of TorontoPluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST)Acus Laboratories GmbHPluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST)Institute of Molecular Biotechnology of the Austrian Academy of SciencesDepartment of Laboratory Medicine, Unit of Clinical Microbiology, Karolinska InstituteAbstract 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.https://doi.org/10.15252/emmm.202013426clinical trialcombination therapyCOVID‐19treatment |
| spellingShingle | Vanessa Monteil Matheus Dyczynski Volker M Lauschke Hyesoo Kwon Gerald Wirnsberger Sonia Youhanna Haibo Zhang Arthur S Slutsky Carmen Hurtado del Pozo Moritz Horn Nuria Montserrat Josef M Penninger Ali Mirazimi Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection EMBO Molecular Medicine clinical trial combination therapy COVID‐19 treatment |
| title | Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection |
| title_full | Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection |
| title_fullStr | Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection |
| title_full_unstemmed | Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection |
| title_short | Human soluble ACE2 improves the effect of remdesivir in SARS‐CoV‐2 infection |
| title_sort | human soluble ace2 improves the effect of remdesivir in sars cov 2 infection |
| topic | clinical trial combination therapy COVID‐19 treatment |
| url | https://doi.org/10.15252/emmm.202013426 |
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