We have synthesized (CPC Scientific, Inc.) four stapled peptides, as depicted in Figure 2. We also synthesized the linear peptide, NYBSP-C, as a control. Besides, we purchased a linear peptide, SBP1, to use as a control, which was reported recently to bind to SARS-CoV-2 RBD with high affinity (KD = 47nM).
Abstract
Human angiotensin-converting enzyme 2 (ACE2) is the primary receptor of SARS-CoV-2 to enter the host cells and start the infection process. Therefore, it is prudent to design therapeutics based on the critical binding region of ACE2, which is a ∼30 aa long helix with a kink in the middle. However, the small peptide in solution may lose its helical conformation and subsequently lose its binding potential to the SARS-CoV-2 RBD, which it utilizes to bind to that helical region. Here we report the design of four stapled peptides based on that helix, which is expected to bind to SARS-CoV-2 with high affinity and prevent the binding of the virus to the ACE2 receptor and disrupt the infection. All stapled peptides showed high helical contents (50-94% helicity). On the contrary, the linear control peptide NYBSP-C showed no helicity (19%). We have evaluated the peptides in a pseudovirus based single-cycle assay in HT1080 and human lung cells, A549. Three of the four stapled peptides showed potent antiviral activity in HT1080 (IC50: 1.9 – 4.1 µM) and A549 cells (IC50: 2.2 – 2.8 µM). It is noteworthy that the stapled peptide, NYBSP-3, which showed the least helical content, also had the lowest antiviral activity in both cell lines. The linear peptides NYBSP-C and SBP1, reported recently to bind SARS-CoV-2 with KD of ∼47nM affinity, showed no antiviral activity. Most significantly, none of the stapled peptides show any appreciable cytotoxicity at the highest dose tested. We determined the proteolytic stability of one of the most active stapled peptides, NYBSP-4, in human plasma, which showed a half-life (T1/2) of >289 min.
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