Computational Design of ACE2-Based Peptide Inhibitors of SARS-CoV-2

Abstract

Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.

Keywords: COVID-19; SARS-CoV-2; molecular dynamics simulations; peptide inhibitors; therapeutics.

Figure 1.

Structural components of the inhibitors designed: (a) inhibitor 1 is composed of α₁ (residues 21 to 55); (b) inhibitor 2 is composed of α₁, α₂, and loose chain between β₃ and β₄ connected by a C–C bond between residues 45 and 351 (residues 21 to 88 and 349 to 357); (c) inhibitor 3 is composed of α₁, α₂, and β₃, β₄ (residues 21 to 105 and 323 to 362); (d) inhibitor 4 has the same composition as inhibitor 3 but different linkage (residues 21 to 95 and 335 to 400); (e) details of inhibitor 3 (c), reorganized with residue 323 connecting residue 105; (f) details of inhibitor 3 (d), reorganized with residue 21 connecting residue 400. (e-f) Conformation of the α-helices and β-sheets was maintained with the rest adapting to the connection. Coloring scheme: red, α-helices; orange, β-sheets or other linker components; blue, RBD of SARS-CoV-2; gray, other parts of ACE2; licorice, the initial contacting residues in the RBD–ACE2 interface.

Figure 2.

(a–e) Final conformations of inhibitors 1, 2, 3, 4, and control. (f) Averaged root-mean-square deviation for the critical amino acids in each inhibitor and for the whole inhibitors when binding with the RBD of SARS-CoV-2. Numbering scale: 1–4, inhibitors 1–4 with RBD; C, control system of PD from ACE2 and the RBD of SARS-CoV-2. (g) Average interaction energies between the contact residues of inhibitors 1–4 (or ACE2) and the RBD of SARS-CoV-2.