ACE2-Based Decoy Receptors for SARS Coronavirus 2

Abstract

SARS-CoV-2 is neutralized by proteins that block receptor-binding sites on spikes that project from the viral envelope. In particular, substantial research investment has advanced monoclonal antibody therapies to the clinic where there are signs of partial efficacy in reducing viral burden and hospitalization. An alternative is to use the host entry receptor, ACE2, as a soluble decoy that broadly blocks SARS-associated coronaviruses with limited potential for viral escape. Here, we summarize efforts to engineer higher affinity variants of soluble ACE2 that rival the potency of affinity-matured antibodies. Strategies have also been used to increase the valency of ACE2 decoys for avid spike interactions and to improve pharmacokinetics via IgG fusions. Finally, the intrinsic catalytic activity of ACE2 for the turnover of the vasoconstrictor angiotensin II may directly address COVID-19 symptoms and protect against lung and cardiovascular injury, conferring dual mechanisms of action unachievable by monoclonal antibodies. Soluble ACE2 derivatives therefore have the potential to be next generation therapeutics for addressing the immediate needs of the current pandemic and possible future outbreaks.

Aptamers as promising nanotheranostic tools in the COVID‐19 pandemic era

“…It was also difficult to suppress SARS‐COV‐2 mutational escape and infections. Multimerization of certain SARS‐COV‐2 biologics such as host receptor ACE2, nanobodies, and single‐chain variable fragments (scFv) into avidity therapeutics have been embraced recently as an effective treatment approach to curb recurrent viral mutation leading to escape issues (Cuesta et al, 2010 ; Jing & Procko, 2021 ; Obeng et al, 2022 ). Therefore, similarly, rational mixtures or cocktails and aptamer multimerization strategies would strongly enhance their binding efficiency (from nanomolar to picomolar range) and improve SARS‐COV‐2 neutralization potency to resist potential viral escape mutation development.…”

“…While these tests are extraordinarily sensitive and provide point‐of‐care results, they suffer drawbacks such as lengthy and costly operational methods, longer turn‐around time, and require technical laboratory training (Carter et al, 2020 ). Also, various biologics such as neutralizing antibodies (Corti et al, 2021 ), nanobodies (Sasisekharan, 2021 ), and soluble Angiotensin‐converting enzyme (ACE2) decoys (Jing & Procko, 2021 ) have been employed to help control and treat the infection. Despite their demonstrated potencies, these biologics are faced with some challenges such as longer, costly, and/or intensive discovery and production methods (Gilchuk et al, 2020 ), reduced efficacies, and antigenic drift due to the emergence of mutational variants (Planas et al, 2021 ).…”

COVID-19 therapies: do we see substantial progress?

“…1 B). Some approaches to solve this question have been reported in the literature (for a review, see [ 76 ]). Full-length recombinant ACE2 (GSK586881) was found safe in a pilot clinical trial as an infusion drug (from 0.1 to 0.8 mg/kg) to treat acute respiratory distress syndrome [ 77 , 78 ] (Table 1 ).…”

“…Another direction is a mutational approach to increase affinity towards spike protein RBD. There are many mutational studies on ACE2 (see review [ 76 ]) to increase the natural affinity towards spike protein RBD. Deep mutagenesis studies enabled the discovery of mutations of residues exposed at the ACE2-spike protein RBD interaction surface that markedly increased the affinity of this binding.…”

Novel ACE2 nanoparticles universally block SARS-CoV-2 variants in the human respiratory tract

“…Even heavily mutated viruses must preserve their ability to bind to this receptor in order to enter their target cells. Presenting hACE2 outside the cell engages the virus, diminishing its cell entry capacity 10 .…”