In-Silico Design of a Novel Tridecapeptide Targeting Spike Protein of SARS-CoV-2 Variants of Concern

Abstract

Several mutations in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have increased the transmission and mortality rate of coronavirus disease-19 (COVID-19) across the globe. Although many vaccines have been developed, a large proportion of the global population remains at high risk of infection. The current study aims to develop an antiviral peptide capable of inhibiting the interaction of SARS-CoV-2 spike protein and its six major variants with the host cell angiotensin-converting enzyme 2 (ACE2) receptor. An in-silico approach was employed to design a therapeutic peptide inhibitor against the receptor-binding domain (RBD) of the spike (S) protein of SARS-CoV-2 and its variants (B.1.1.7, B.1.351, P.1, B.1.617.1, B.1.617.2 and B.1.617.3). The binding specificity and affinity of our designed peptide inhibitor Mod13AApi (YADKYQKQYKDAY) with wild-type S-RBD and its six variants was confirmed by molecular docking using the HPEPDOCK tool, whereas complex stability was determined by the MD simulation study. The physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of inhibitory peptides were determined using the ExPASy tool and pkCSM server. The docking results and its properties from our in-silico analysis present the Mod13AApi, a promising peptide for the rapid development of anti-coronavirus peptide-based antiviral therapy. Blockage of the binding of the spike protein of SARS-CoV-2 variants with ACE2 in the presence of the therapeutic peptide may prevent deadly SARS-CoV-2 variants entry into host cells. Therefore, the designed inhibitory peptide can be utilized as a promising therapeutic strategy to combat COVID-19, as evident from this in-silico study.

Development and Evaluation of Peptidomimetic Compounds against SARS‐CoV‐2 Spike Protein: An in silico and in vitro Study

“…The other in silico investigation was aimed to design a peptide‐based inhibitor named Mod13AApi with the potential to interfere with the attachment of spike protein of SARS‐CoV‐2 and its variants to ACE2. In this work, by employing molecular docking experiment, some similar interactions were also predicted for this tridecapeptide in complex with spike protein and its variants like the interactions anticipated for our study [28] . In 2021, Acharya and colleagues reported a study in which two potential compounds (called MU‐UNMC‐1 and MU‐UNMC‐2) as entry inhibitors for SARS‐CoV‐2 and its variants were discovered using virtual screening technique.…”

“…In this work, by employing molecular docking experiment, some similar interactions were also predicted for this tridecapeptide in complex with spike protein and its variants like the interactions anticipated for our study. [28] In 2021, Acharya and colleagues reported a study in which two potential compounds (called MU‐UNMC‐1 and MU‐UNMC‐2) as entry inhibitors for SARS‐CoV‐2 and its variants were discovered using virtual screening technique. These molecules were experimentally evaluated in a live SARS‐CoV‐2 infection assays.…”

“…Beta, Gamma, and Delta+ variants of SARS‐CoV‐2 have Lys 417 mutation while Gly 496 is mutated in the case of Omicron variant. [ 28 , 30 ] According to the possible conformational change induced by some mutations in the binding pocket of spike protein, the interactions of PM1 and PM2 might be influenced. In silico and in vitro studies of the selected peptidomimetic molecules with different SARS‐CoV‐2 variants could be of great importance for providing valuable information useful in rationally design of molecules against spike protein of SARS‐CoV‐2, however it is beyond of this study and could be an interesting topic for future studies.…”

“…None of the predicted residues of spike protein engaged in the interactions with PM1 and PM2 are mutated in the known SARS‐CoV‐2 variants including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Kappa (B.1.617.1), Delta (B.1.617.2), Delta+ (B.1.617.3), and Omicron ((B.1.1.529) variants, with the exception of Lys 417 and Gly 496 . Beta, Gamma, and Delta+ variants of SARS‐CoV‐2 have Lys 417 mutation while Gly 496 is mutated in the case of Omicron variant [28,30] . According to the possible conformational change induced by some mutations in the binding pocket of spike protein, the interactions of PM1 and PM2 might be influenced.…”

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

“…Therefore, current research is also focused on developing alternative, smaller molecules capable of interfering with the interaction of the SARS-CoV-2 spike protein with cellular ACE2 [ 12 , 13 , 14 , 15 ]. Over the past two years, a range of studies have reported the computational design of smaller proteins or peptides, either based on the structure of the two N-terminal α-helices of ACE2, through which it contacts the receptor binding domain (RBD) of the SARS-CoV-2 spike protein [ 16 , 17 , 18 , 19 ], or through de novo design based on the RBD structure [ 19 , 20 , 21 ]. In a mechanism similar to antibodies, such peptides and miniproteins can be expected to bind to RBD, preventing its interaction with ACE2, thus blocking infection.…”