In Silico Design of Peptide-Based SARS-CoV-2 Fusion Inhibitors That Target WT and Mutant Versions of SARS-CoV-2 HR1 Domains

Abstract

In 2019, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began infecting humans, resulting in the COVID-19 pandemic. While the push for development of vaccines has yielded some positive results, the emergence of additional variants has led to concerns surrounding sustained vaccine effectiveness as the variants become the dominant strains. This work was undertaken to develop peptide-based antivirals capable of targeting both the wildtype (WT) heptad repeat 1 (HR1) domain of SARS-CoV-2 and the new HR1 variants which have developed. In silico protein mutagenesis, structural characterization, and protein–protein molecular docking were utilized to determine molecular interactions which facilitated binding of peptide-based antivirals targeting the HR1 domains. Molecular dynamics simulations were utilized to predict the final binding affinities of the top five peptide inhibitors designed. This work demonstrated the importance of hydrophobic interactions in the hydrophobic gorge and in the rim of the HR1 domain. Additionally, the placement of charged residues was shown to be essential in maximizing electrostatic interactions. The top five designed peptide inhibitors were all demonstrated to maintain good binding affinity to the WT and the variant HR1 SARS-CoV-2 domains. Therefore, the peptide inhibitors designed in this work could serve as potent antivirals which are effective in targeting both the original SARS-CoV-2 and the HR1 variants that have developed.

Design and selection of peptides to block the SARS-CoV-2 receptor binding domain by molecular docking

“…These results are similar to previous reports in which short peptides were docked to RBD [ 14 ]. However, the binding energy reported in the present research contrasts with several studies that reported higher binding energies between the theoretical peptides and RBD [ 62 – 63 ], probably due to the software used in the molecular docking calculations. However, these reports did not show the binding energy of the ACE2–RBD complex.…”

“…The peptide net charge, isoelectric point, and water solubility for peptides were determined by the on-line software INNO-VAGEN's peptide calculator (PEPCALC). Almost all OAPs are soluble in aqueous media, independently on their isoelectric point, due to the high ratio between hydrophilic and hydrophobic amino acid residues, except the peptides temporin B and lysozyme (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80). The net charge calculated for the OAPs varies according to the number of negatively and positively charged amino acids present in the primary structure.…”

The Healing Power of Clean Rivers: In Silico Evaluation of the Antipsoriatic Potential of Apiin and Hyperoside Plant Metabolites Contained in River Waters

“…Herein, we aim at discussing the potential benefits provided by clean rivers on human health from a therapeutic perspective using in silico techniques to show that some secondary plant metabolites which are relatively abundant in river waters could provide benefits in the treatment of psoriasis. To this aim, conscious of the role of molecular docking (MD) in the exploration of biomedically-relevant molecular interactions, we conducted an MD study with the program HDOCK [ 20 , 21 , 22 , 23 , 24 , 25 ] using the 3D structures of NF-kB, IL-17 and IL-36, that are the protein targets involved in psoriasis [ 26 ] and those from three plant metabolites found in rivers. HDOCK is used for both macromolecule-macromolecule [ 20 , 21 , 22 , 23 ] and small molecule-macromolecule [ 24 ] dockings, with types of macromolecules including proteins.…”

“…HDOCK is used for both macromolecule-macromolecule [ 20 , 21 , 22 , 23 ] and small molecule-macromolecule [ 24 ] dockings, with types of macromolecules including proteins. HDOCK score furnished by the program is an energy score whose values are listed dimensionless [ 25 ] and larger negative numbers of HDOCK score indicate stronger binding interactions between the interacting ligand/macromolecules, which was reported to correlate well to experimental binding affinities [ 25 ]. Different flavonoids and their glycosilated forms ( Figure 1 ) were identified by liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) as secondary plant metabolites released into river waters from riparian vegetation at concentrations up to about 5 µg/L [ 27 ].…”

A Collection of Designed Peptides to Target SARS-CoV-2 Spike RBD—ACE2 Interaction

“…In the context of viral infection examples such as the FDA-approved peptide Enfurvirtide [16] and further research (reviewed in [17,18]) illustrate the use of peptides as potential agents to block PPIs. In fact, a number of recent publications has shown promising results on the use of peptides to blocks the entrance of SARS-CoV-2 virus using peptides derived from native element of the interaction humanACE2 and SARS-CoV-2 spike [19][20][21] including designed peptides targeting of the heptad repeat 1 region [22], the RBD domain [23][24][25], with validation in cell-cultures [26,27] and tissues [28]. While these approaches rely on the sequence diversification of existing native elements, ours complements these efforts by providing novel sequences (next).…”