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 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.

The renin-angiotensin system and specifically angiotensin-converting enzyme 2 as a potential therapeutic target in SARS-CoV-2 infections

“…From a molecular pharmacological point of view, administration of rhACE2 activates the Ang 1–7 and Ang 1–9 synthesis pathway of the RAS system (non-classical pathway) by decreasing Ang II levels with a tendency to lower the concentration of proinflammatory cytokines (Gaddam et al 2014 ). Some clinical trials show excellent results when administered in combination rhACE2 and remdesivir (Monteil et al 2021 ). Theoretically, administration of soluble ACE2 protein, in sufficient quantities, binding to the spike protein of SARS-CoV-2, could reduce the attachment to ACE-2 at the plasma membrane.…”

Organoids: A New Model for SARS-CoV-2 Translational Research

“…Monteil et al (46) developed a kidney organoid model with high ACE2 expressions, which was highly consistent with the renal tissue structure within two weeks after six days of SARS-CoV-2 infection, the level of SARS-CoV-2 RNA in the supernatant of the renal organoid markedly increased, indicating that the kidney was vulnerable to the virus invasion. To illustrate whether SARS-CoV-2 invades renal cells via ACE2, they added a trial drug human recombinant soluble ACE2 (hrsACE2) to competitively binding to the virus rather than host cells (47). As a result, the SARS-CoV-2 load decreased by about 1000-5000 times in a dose-dependent manner compared with the blank control group.…”

The Fight against COVID-19 on the Multi-Protease Front and Surroundings: Could an Early Therapeutic Approach with Repositioning Drugs Prevent the Disease Severity?

“…According to Zoufaly et al [93], the administration of recombinant sACE2 could act through two mechanisms either by binding to S protein and neutralizing the viral particles and the other by increasing the concentration of angiotensin II, thus helping to reduce multi-organ damage. In addition, Monteil et al [94] showed that the administration of recombinant soluble ACE2 along with the antiviral remdesivir has an additive effect at sub-toxic concentrations and may improve the effect of remdesivir during SARS-CoV-2 infection.…”