Identification of a Potential Peptide Inhibitor of SARS-CoV-2 Targeting its Entry into the Host Cells

Abstract

Background and objective: Coronavirus disease (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to the incessant spread of the disease with substantial morbidity and mortality rates, there is an urgent demand for effective therapeutics and vaccines to control and diminish this pandemic. A critical step in the crosstalk between the virus and the host cell is the binding of SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cells. Hence, inhibition of this interaction could be a promising strategy to combat the SARS-CoV-2 infection.

Methods: Docking and Molecular Dynamics (MD) simulation studies revealed that designed peptide maintains their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2.

Results: We have designed a novel peptide that could inhibit SARS-CoV-2 spike protein interaction with ACE2, thereby blocking the cellular entry of the virus.

Conclusion: Our findings suggest that computationally developed inhibitory peptide may be developed as an anti-SARS-CoV-2 agent for the treatment of SARS-CoV-2 infection. We further plan to pursue the peptide in cell-based assays and eventually for clinical trials.

Fig. 1

ACE2 is an entry receptor for SARS-CoV-2. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, ACE2 angiotensin-converting enzyme 2

Fig. 2

SARS-CoV-2 interaction with the ACE2 PD domain (6M17). The projected view displays the interacting residues at the interface site. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, ACE2 angiotensin-converting enzyme 2, PD peptidase domain

Fig. 3

Identification of critically important residues in the 23aa peptide by alanine scanning, and the binding energies of each peptide docked with SARS-CoV-2 spike protein predicted by pyDockWEB. The alanine scanning results provide the 18aa new peptide inhibitor with similar binding efficiency

Fig. 4

SARS-CoV-2 (Cyan) interaction with the 18aa-derived peptide (blue) along with the original peptide of 23-amino acid (red). Dockings were performed using different software packages: a pyDock; b ZDOCK; and c HADDOCK 2.4. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

Fig. 5

a Plots of backbone RMSD of the 23aa and 18aa peptide, shown in magenta and green, respectively. b The 23aa and 18aa peptides complexed with SARS-CoV-2. RMSD root mean square deviation, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2