ACE2‐based decoy receptors for SARS coronavirus 2

Abstract

SARS coronavirus 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 they have shown partial efficacy in reducing viral burden and hospitalization. An alternative is to use the host entry receptor, angiotensin‐converting enzyme 2 (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.

Anti-SARS-CoV-1 and −2 nanobody engineering towards avidity-inspired therapeutics

“…The fusion of molecules to Fc domains of human immunoglobulin (Ig) is not uncommon because the fused Fc passes on antibody-like characteristics such as the recruitment of effector functions, complement activation and long serum circulatory half-life to resultant molecules [66] , [67] , [68] , [69] . Moreover, in relation to coronavirus disease, the approach multimerizes the efficiency and neutralization potency of ACE2 decoys and antibodies, as reviewed elsewhere [70] , [71] , [72] .…”

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

“…These findings challenge whether monoclonal antibodies are suitable over the long term for the treatment of endemic COVID-19. An alternative approach is to use soluble decoy receptors that bind and block the RBD (Monteil et al, 2020;Jing & Procko, 2021;Chan et al, 2020;Hofmann et al, 2004;Lei et al, 2020). S binds to angiotensin-converting enzyme 2 (ACE2), which is highly expressed on type II alveolar lung epithelium (Hamming et al, 2004;Zhao et al, 2020), triggering conformational changes that facilitate fusion of the viral envelope and host cell membrane (Huang et al, 2020).…”

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).…”