Human angiotensin-converting enzyme 2 (ACE2)-based stapled peptide effectively inhibits SARS-CoV-2 infection in vitro
Human angiotensin-converting enzyme 2 (ACE2) is the main receptor for SARS-CoV-2 to enter host cells and initiate the infection process, so it is very wise to design drug molecules based on the key binding site of ACE2, which It is a helical structure of about 30 amino acid residues with a kink in the middle. Small peptides easily lose their helical conformation in solution, and the ability to rely on the helical conformation to bind to the SARS-CoV-2 RBD is also lost. This paper reports four staple peptides designed based on this helical structure, the latter is expected to have a high affinity with SARS-CoV-2, thereby inhibiting the binding of the virus to the ACE2 receptor, and ultimately interrupting the infection process. All stapled peptides had high helicity content (50-94% helicity), while the control linear peptide NYBSP-C had almost no helicity (19%). The antiviral activity of these four stapled peptides in HT1080 and human lung cells A549 was also evaluated using a pseudovirus-based single-cycle infection assay, three of which were in HT1080 cell line (IC50: 1.9~4.1) and A549 cell line ( IC50: 2.2~2.8) have good antiviral activity. Notably, NYBSP-3, the staple peptide with the least helicity, also had the lowest antiviral activity in the two cell lines mentioned above. The recently reported linear peptides NYBSP-C and SBP1 had KD values of ~47 nM with SARS-CoV-2 and showed no antiviral activity. Most importantly, none of the above-mentioned stapled peptides were significantly cytotoxic even at the highest doses tested. The enzymatic stability of one of the most active stapled peptides, NYBSP-4, was also determined, and its half-life (T1/2) in human plasma was greater than 289 min.
Protein-Protein Interaction (PPI) is involved in the regulation of many important cellular processes in organisms, such as cell proliferation, division, apoptosis, necrosis, and protein transcription and translation.