Abstract
The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 “knock-in” mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and “alanine walk” studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and “broad-spectrum” management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.
Highlights
In the last 20 years, coronaviruses have caused three major transmissible disease outbreaks in human, including severe acute respiratory syndrome (SARS),[1] Middle East respiratory syndrome (MERS)[2], and coronavirus disease 2019 (COVID-19).[3,4]One of the challenges to control coronaviruses is that they evolve constantly, even though slower than HIV and influenza.[5]
BALB/c mice were immunized with Fc-tagged human angiotensin-converting enzyme 2 (ACE2) potent than 3E8, as suggested by the difference between their IC50 protein and the sera were screened for binding to ACE2 values (2.3 vs. 0.04 nM), even though both completely abolished and blocking of SARS-CoV-2 S1-subunit SARS-CoV-2 replication at high concentrations (Fig. 4a)
We revealed a broadspectrum anti-coronavirus epitope on ACE2
Summary
In the last 20 years, coronaviruses have caused three major transmissible disease outbreaks in human, including severe acute respiratory syndrome (SARS),[1] Middle East respiratory syndrome (MERS)[2], and coronavirus disease 2019 (COVID-19).[3,4]. BALB/c mice were immunized with Fc-tagged human ACE2 potent than 3E8, as suggested by the difference between their IC50 protein and the sera were screened for binding to ACE2 values (2.3 vs 0.04 nM), even though both completely abolished (supplementary Fig. 1a) and blocking of SARS-CoV-2 S1-subunit SARS-CoV-2 replication at high concentrations (Fig. 4a). 3E8 has no effects on ACE2’s catalytic activities or causes toxicity in “knock-in” mice Since ACE2 plays important roles in maintaining blood pressure homeostasis in the renin-angiotensin system, we evaluated the safety risks of 3E8 application both in vitro and in vivo Our studies with both recombinant ACE2 protein and Vero E6 cells suggested that 3E8 had no effects on ACE2’s catalytic activities even at 666.7 nM (Fig. 5a, b). Evolutionary tree of 3E8 binding site on ACE2 with different species was provided (Fig. 6h), and phylogenetic diversities at position 23, 24, 31, and 34 were identified
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