Targeting the Receptor-Binding Motif of SARS-CoV‑2 with D‑Peptides Mimicking the ACE2 Binding Helix: Lessons for Inhibiting Omicron and Future Variants of Concern

• Published in: Journal of chemical information and modeling Vol. 62; no. 15; pp. 3618 - 3626
• Main Authors: Valiente, Pedro A., Nim, Satra, Lee, JinAh, Kim, Seungtaek, Kim, Philip M.
• Format: Journal Article
• Language: English
• Published: Washington American Chemical Society 08.08.2022
• Subjects: Binding; Computational Biochemistry; COVID-19; Inhibitors; Monoclonal antibodies; Mutation; Peptides; Receptors; Severe acute respiratory syndrome coronavirus 2; Viral diseases
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.2c00500

The COVID-19 pandemic continues to spread around the world, with several new variants emerging, particularly those of concern (VOCs). Omicron (B.1.1.529), a recent VOC with many mutations in the spike protein’s receptor-binding domain (RBD), has attracted a great deal of scientific and public interest. We previously developed two D-peptide inhibitors for the infection of the original SARS-CoV-2 and its VOCs, alpha and beta, in vitro. Here, we demonstrated that Covid3 and Covid_extended_1 maintained their high-affinity binding (29.4–31.3 nM) to the omicron RBD. Both D-peptides blocked the omicron variant in vitro infection with IC50s of 3.13 and 5.56 μM, respectively. We predicted that Covid3 shares a larger overlapping binding region with the ACE2 binding motif than different classes of neutralizing monoclonal antibodies. We envisioned the design of D-peptide inhibitors targeting the receptor-binding motif as the most promising approach for inhibiting current and future VOCs of SARS-CoV-2, given that the ACE2 binding interface is more limited to tolerate mutations than most of the RBD’s surface.