Document text
Principal Investigator: AILONG KE
Organization: CORNELL UNIVERSITY
Fiscal Year: 2022
Award: $686,255
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The current SARS-CoV-2 pandemic poses an immediate and global public health threat. This is the third major
zoonotic-born coronavirus outbreak in humans in the past twenty years, after SARS-CoV-1 and MERS-CoV.
Because mainstream antiviral approaches such as vaccines and neutralizing antibodies have to be specifically
developed for each virus, there has always been a lag in effective medical remedy, which resulted in grave
human death toll and economic disruption. Since viruses rarely switch their receptor specificity, here we
propose a therapeutic strategy that utilizes the trimeric receptor as a decoy to neutralize the virus. SARS-CoV-
1 and SARS-CoV-2 target the angiotensin-converting enzyme 2 (ACE2) to gain cell entry. The “tri-ACE2”
decoys are designed in a structure-guided fashion to match the symmetry and geometry of the viral spike (S),
which maximizes the binding affinity through the trimer avidity effect. Additional functional domains are then
introduced into the tri-ACE2 platform to achieve better antiviral activity. We present strong preliminary data
demonstrating the effectiveness of such designs. Tri-ACE2 decoys lock the viral spikes in a symmetric “3-UP”
receptor binding domain (RBD) conformation, neutralizing various ACE2-tropic coronaviruses with nanomolar
concentrations, ~100-fold better than monomeric ACE2. Replacing ACE2 with ab initial designed minibinders
(miniature-ACE2s) further improved the IC50 to ~20 pM by enabling ultrafast S-binding. The advantage of tri-
ACE2 over neutralizing antibodies lies in its potential broad-spectrum activity against all ACE2-tropic
coronaviruses, and in its expected resistance against evader mutations in the viral receptor. Therefore, this line
of inhibitors can potentially serve as an off-the-shelf therapeutic in future outbreaks caused by unknown ACE2-
tropic coronaviruses. We propose to explore the full potential of the structure-guided receptor multimerization
as a general antiviral strategy. These efforts will also generate new mechanistic insight about how the
coronavirus spike protein functions in general. The specific aims include: 1) Produce potent and evader-
resistant tri-ACE2 inhibitors against SARS-CoV-2; 2) Produce tri-miniatureACE2 with picomolar inhibitory
activity and novel antiviral mechanism; 3) Determine the efficacy of tri-ACE2 against SARS-CoV-2 and related
viruses in primary airway cell cultures and animal models; 4) Determine the prophylactic and therapeutic
efficacy of tri-ACE2 based inhibitors against SARS-CoV-2 infection in a Golden Syrian hamster model. Upon
the completion of this project, we expect that we will have developed safe, highly effective, and broad-
spectrum anti-coronavirus drugs that can directly lead to trials in nonhuman primates or humans.
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disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Specificity><Structure><Syrian Hamsters><Testing><Therapeutic><Treatment Efficacy><Viral><Viral Receptor><Virus><Virus Receptors><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><achievement Mainstream Education><active followup><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><cell culture><cell cultures><clinical relevance><clinically relevant><conformation><conformational conversion><conformational state><conformational transition><corona 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