Abstract
SARS-CoV-2 is coronavirus causing COVID-19 pandemic. To enter human cells, receptor binding domain of S1 subunit of SARS-CoV-2 (SARS-CoV-2-RBD) binds to peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptor. Employing peptides to inhibit binding between SARS-CoV-2-RBD and ACE2-PD is a therapeutic solution for COVID-19. Previous experimental study found that 23-mer peptide (SBP1) bound to SARS-CoV-2-RBD with lower affinity than ACE2. To increase SBP1 affinity, our previous study used residues 21–45 of α1 helix of ACE2-PD (SPB25) to design peptides with predicted affinity better than SBP1 and SPB25 by increasing interactions of residues that do not form favorable interactions with SARS-CoV-2-RBD. To design SPB25 with better affinity than ACE2, we employed computational protein design to increase interactions of residues reported to form favorable interactions with SARS-CoV-2-RBD and combine newly designed mutations with the best single mutations from our previous study. Molecular dynamics show that predicted binding affinities of three peptides (SPB25Q22R, SPB25F8R/K11W/L25R and SPB25F8R/K11F/Q22R/L25R) are better than ACE2. Moreover, their predicted stabilities may be slightly higher than SBP1 as suggested by their helicities. This study developed an approach to design SARS-CoV-2 peptide binders with predicted binding affinities better than ACE2. These designed peptides are promising candidates as SARS-CoV-2 inhibitors.
Highlights
COVID-19 pandemic has caused large numbers of cases and deaths globally, and it is caused by SARS-CoV-2 that initially uses its SARS-CoV-2-receptor binding domain (RBD) to bind to angiotensin-converting enzyme 2 (ACE2)-peptidase domain (PD) to enter human cells
The aim of this study is to further increase the binding affinities of 25-mer peptides so that their predicted binding affinities are better than human ACE2 receptor using computational protein design (Rosetta) and molecular dynamics (MD) (AMBER)
Using SPB25 as a designed template and reference, our design strategy is to enhance the binding affinity of residues that were previously reported to form favorable interactions between residue 21–45 of ACE2 peptidase domain (ACE2-PD) and SARS-CoV-2-RBD29,37 and combine the newly designed single mutations with the best designed single mutations ( SPB25F8N, SPB25F8R and SPB25L25R) from our previous study to further increase the binding affinities of designed peptides so that their predicted binding affinities are better than human ACE2 receptor
Summary
To increase SBP1 affinity, our previous study used residues 21–45 of α1 helix of ACE2-PD (SPB25) to design peptides with predicted affinity better than SBP1 and SPB25 by increasing interactions of residues that do not form favorable interactions with SARS-CoV-2-RBD. This study developed an approach to design SARS-CoV-2 peptide binders with predicted binding affinities better than ACE2. Disrupting the protein–protein binding interfaces of SARS-CoV-2-RBD and ACE2-PD to prevent coronavirus entry in human cells is a promising therapeutic solution for COVID-19. Peptides or small proteins with high binding affinity to SARS-CoV-2-RBD could have advantages over antibodies for direct delivery into the respiratory system via intranasal administration, nebulization or dry powder aerosol because of their smaller sizes and higher density of inhibitory d omains[15]. Previous study reported that small proteins with high binding affinity to the influenza hemagglutinin when delivered intranasally can provide prophylactic and therapeutic protection in rodent models of lethal influenza infection[28]
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