ABSTRACT
COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects host cells by binding its viral spike protein receptor-binding domain (RBD) to the angiotensin converting enzyme 2 (ACE2) on host cells. Blocking the SARS-CoV-2-RBD/ACE2 interaction is, therefore, a potential strategy to inhibit viral infections. Using a novel biopanning strategy, a small anti-ACE2 peptide is discovered, which shows high affinity and specificity to human ACE2. It blocks not only the SARS-CoV-2-RBD/ACE2 interaction but also the SARS-CoV-1-RBD/ACE2 interaction. Moreover, it inhibits SARS-CoV-2 infection in Vero-E6 cells. The peptide shows negligible cytotoxicity in Vero-E6 cells and Huh7 cells. In vivo short-term lung toxicity study also demonstrates a good safety of the peptide after intratracheal administration. The anti-ACE2 peptide can be potentially used as a prophylactic or therapeutic agent for SARS-CoV-2 or other ACE2-mediated viruses. The strategy used in this study also provides a fast-track platform to discover other antiviral peptides, which will prepare the world for future pandemics.