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

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.