COVID-19 became a worldwide pandemic shortly after the first emergence of SARS-CoV-2 in December 2019. The virus possesses a high dynamic of evolution, with several mutations have been occurred and many variations of concern (VOCs). The infection is initiated by the interaction of SARS-CoV-2 receptor binding domain (RBD) and hACE2. ACE2 converts angiotensin I to angiotensin 1-9, and hACE2 is the receptor for the spike of SARS-CoV-2. The RBD is immunodominant, this region is the target of vaccine, antibodies, and peptides design. RBD is the poorly conserved region of S protein, the mutations in RBD resulted in many immune escapes, and the approved antibodies lost their susceptibility. In this study, the neutralizing effect of neutralizing peptides CSNP1, CSNP4 and Pep1 was measured in vitro, using the model of HEK293 cells that highly expresses hACE2 as the host cell, and lentiviruses that carry the SARS- CoV-2 spike proteins on their surface as the pseudovirus particles. The results showed that all CSNP1, CSNP4 and Pep1 strongly inhibit the infection of SARS- CoV-2 and have neutralizing effects on all VOCs. The peptides work in dose- dependent manner and do show cytotoxicity even in high concentrations. Taken together, neutralizing peptides based of the structure of hACE2 universally deter the SARS-CoV-2 infections, and the three neutralizing peptides CSNP1, CSNP4, and pep1 are promising candidates in treatment of the new emerging SARS-CoV-2 variants and ready to go in clinical tests.
