Passivating the Omicron SARS-CoV-2 variant with self-assembled nano peptides: Specificity, stability, and no cytotoxicity

The SARS-CoV-2 Omicron variant is called a “variant of concern” (VOC) which has spread all over the world at a faster rate than even the first SARS-CoV-2 outbreak despite travel restrictions. In order to combat the health consequences from a SARS-CoV-2 Omicron variant infection, the objective of the present in vitro study was to develop self-assembled nano peptides to attach to the virus and inhibit its attachment and entry into mammalian cells for replication. For this purpose, two amphipathic peptides containing hydrophobic and hydrophilic peptides and an unnatural amino acid (such as 2-aminoisobutyric acid (U)) were designed to attach to the less mutated virus envelope rather than more frequently mutated S-protein region: NapFFTLUFLTUTEKKKK and NapFFMLUFLMUMEKKKK. These peptides were synthesized using the solid phase peptide synthesis method and were characterized for mammalian cell infection using well-established pseudo virus assays. In vitro results showed that the two self-assembled nano peptides significantly inhibited the ability of the SARS-CoV-2 Omicron variant virus to infect mammalian cells and replicate with IC50 values of 0.5 and 360 mg/ml for NapFFTLUFLTUTEKKKK and NapFFMLUFLMUMEKKKK, respectively. Most impressively, 1 mg/ml of NapFFTLUFLTUTEKKKK resulted in a 2 log reduction in pseudovirus replication after just 15 min at a viral load of 10(6) copies/ml. Results further confirmed that the peptides continued to passivate the SARS-CoV-2 Omicron variant for up to one week and were stable in cell culture media before being added to the virus. Mechanistically, in vitro results showed selective binding of the peptides to the SARS-CoV-2 Omicron variant envelop protein over the more frequently mutated spike protein up to one week demonstrating the stability of the peptides. Cytotoxicity studies with fibroblasts also showed no toxicity when exposed to the peptides for 72 h. In summary, the present results strongly suggest that the two peptides developed in this study should be further researched for a wide range of anti-SARS-CoV-2 virus applications, including the present Omicron and future mutations.