Computational Design of 25-mer Peptide Binders of SARS-CoV-2

Abstract

SARS-CoV-2 is the novel coronavirus causing the COVID-19 pandemic. To enter human cells, the receptor-binding domain (RBD) of the S1 subunit of SARS-CoV-2 (SARS-CoV-2-RBD) initially binds to the peptidase domain of angiotensin-converting enzyme 2 receptor (ACE2-PD). Using peptides to inhibit SARS-CoV-2-RBD binding to ACE2 is a potential therapeutic solution for COVID-19. A previous study identified a 23-mer peptide (SBP1) that bound to SARS-CoV-2-RBD with comparable K D to ACE2. We employed computational protein design and molecular dynamics (MD) to design SARS-CoV-2-RBD 25-mer peptide binders (SPB25) with better predicted binding affinity than SBP1. Using residues 21−45 of the α1 helix of ACE2-PD as the template, our strategy is employing Rosetta to enhance SPB25 binding affinity to SARS-CoV-2-RBD and avoid disrupting existing favorable interactions by using residues that have not been reported to form favorable interactions with SARS-CoV-2-RBD as designed positions. Designed peptides with better predicted binding affinities, by Rosetta, than SPB25 were subjected to MD validation. The MD results show that five designed peptides (SPB25 F8N , SPB25 F8R , SPB25 L25R , SPB25 F8N/L25R , and SPB25 F8R/L25R ) have better predicted binding affinities, by the MM-GBSA method, than SPB25 and SBP1. This study developed an approach to design SARS-CoV-2-RBD peptide binders, and these peptides may be promising candidates as potential SARS-CoV-2 inhibitors.

Native Structure-Based Peptides as Potential Protein–Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor

“…All of our peptides are based on the subsequence of the α1-helix ACE2 region [ 23 ], which have also been utilized in similar peptide-based strategies described elsewhere [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. It is worthwhile to notice that peptides proposed by other groups are based on the assumption that larger parts of the interaction interface should be mimicked to retain strong binding affinity to S protein.…”

“…Peptides derived from native protein–protein interaction (PPI) sites of interacting partners are valuable starting points in developing effective inhibitors of protein–protein interactions, and have already been proven to be useful for the design of efficient PPI modulators [ 11 , 12 ]. As ACE2-S complex structures have been solved by experimental techniques, a rational starting point for the development of molecules disrupting the formation of protein–protein of the complex is available, and has already been utilized to propose several peptides against SARS-CoV [ 13 , 14 ], and even recently SARS-CoV-2 [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

SARS-CoV-2 spike protein: pathogenesis, vaccines, and potential therapies

“…Inhibiting the large interface of RBD by small drug molecules is usually not effective and challenging [ 92 , 114 ]. Alternatively, peptides can be utilized as they have a larger surface area, allowing more functional groups to interact with the binding site, therefore mimicking and blocking these native protein–protein interactions [ 92 ]. Additionally, peptides can be used to inhibit the formation of the six-helical bundle (6-HB) of S protein [ 69 ].…”

Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

“…Another intriguing study was done by Sitthiyotha and Chunsrivirot. 30 These authors cleverly combined computational protein design (Rosetta) and MD simulations (AMBER) to generate a library of 25-mer peptides based on residues 21–45 of the α1 helix of hACE2. Their results predict that their peptides will display higher affinity toward the SARS-CoV-2-RBD than the peptides developed by the Pentelute group.…”