Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Currently, as dangerous mutations emerge, there is an increased demand for specific treatments for SARS-CoV-2 infected patients. The spike glycoprotein on the virus envelope binds to the angiotensin converting enzyme 2 (ACE2) on host cells through its receptor binding domain (RBD) to mediate virus entry. Thus, blocking this interaction may inhibit viral entry and consequently stop infection. Here, we generated fusion proteins composed of the extracellular portions of ACE2 and RBD fused to the Fc portion of human IgG1 (ACE2-Ig and RBD-Ig, respectively). We demonstrate that ACE2-Ig is enzymatically active and that it can be recognized by the SARS-CoV-2 RBD, independently of its enzymatic activity. We further show that RBD-Ig efficiently inhibits in-vivo SARS-CoV-2 infection better than ACE2-Ig. Mechanistically, we show that anti-spike antibody generation, ACE2 enzymatic activity, and ACE2 surface expression were not affected by RBD-Ig. Finally, we show that RBD-Ig is more efficient than ACE2-Ig at neutralizing high virus titers. We thus propose that RBD-Ig physically blocks virus infection by binding to ACE2 and that RBD-Ig should be used for the treatment of SARS-CoV-2-infected patients.
Highlights
SARS-CoV-2 was first reported in December 2019 in China
We showed that the fusion proteins bind
We propose that receptor binding domain (RBD)-Ig physically blocks virus infection by binding to angiotensin converting enzyme 2 (ACE2) and it may be used for the treatment of SARS-CoV-2-infected patients
Summary
SARS-CoV-2 was first reported in December 2019 in China It is a highly contagious virus which had caused worldwide socio-economic, political, and environmental problems [1]. In an attempt to stop the pandemic, the FDA first issued an emergency use authorization for Pfizer [2] and Moderna [3] vaccines, followed by Ad26.COV2.S [4]. Both the Pfizer vaccine, called BNT162b2 [5], and the Moderna vaccine, called mRNA-1273 [6], are composed of a lipid-nanoparticle (LNP)–encapsulated mRNA expressing the prefusion-stabilized spike glycoprotein. The virus binds primarily to ACE2 receptors on type 2 pneumocytes [9] and mainly targets the lungs, but as ACE2 is present on many other cells, the virus is capable of causing damage to other organs such as the heart, the liver, the kidneys, blood, and immune system [10]
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