Key result
An engineered trimeric ACE2 (T-ACE2) protein scaffold binds the SARS-CoV-2 trimeric spike protein with extremely high affinity (KD < 1 pM) and potently inhibits SARS-CoVs and mutants.
Why the study?
SARS-CoV-2 requires ACE2 binding for infectivity, motivating the development of inhibitors to prevent mutational escape and prepare for future coronavirus outbreaks.
An engineered trimeric ACE2 protein scaffold demonstrates extremely high binding affinity to the SARS-CoV-2 spike protein and potently neutralizes the virus and its mutants in vitro.
SARS-CoV-2 enters cells via ACE-2, which binds the spike protein with moderate affinity. Despite a constant background mutational rate, the virus must retain binding with ACE2 for infectivity, providing a conserved constraint for SARS-CoV-2 inhibitors. To prevent mutational escape of SARS-CoV-2 and to prepare for future related coronavirus outbreaks, we engineered a de novo trimeric ACE2 (T-ACE2) protein scaffold that binds the trimeric spike protein with extremely high affinity (K D < 1 pM), while retaining ACE2 native sequence. T-ACE2 potently inhibits all tested pseudotyped viruses including SARS-CoV-2, SARS-CoV, eight naturally occurring SARS-CoV-2 mutants, two SARSr-CoVs as well as authentic SARS-CoV-2. The cryo-EM structure reveals that T-ACE2 can induce the transit of spike protein to “three-up” RBD conformation upon binding. T-ACE2 thus represents a promising class of broadly neutralizing proteins against SARS-CoVs and mutants.
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Guo et al. (2020) studied SARS-CoV-2 infection. Engineered trimeric ACE2 (T-ACE2) protein scaffold was evaluated on Binding affinity to trimeric spike protein (KD < 1 pM). An engineered trimeric ACE2 (T-ACE2) protein scaffold binds the SARS-CoV-2 trimeric spike protein with extremely high affinity (KD < 1 pM) and potently inhibits SARS-CoVs and mutants.
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