Computational Design of Potent D‑Peptide Inhibitors of SARS-CoV‑2

Blocking the association between
the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain (RBD)
and the human angiotensin-converting enzyme 2 (ACE2) is an attractive
therapeutic approach to prevent the virus from entering human cells.
While antibodies and other modalities have been developed to this
end, d-amino acid peptides offer unique advantages, including
serum stability, low immunogenicity, and low cost of production. Here,
we designed potent novel D-peptide inhibitors that mimic the ACE2
α1-binding helix by searching a mirror-image version of the
PDB. The two best designs bound the RBD with affinities of 29 and
31 nM and blocked the infection of Vero cells by SARS-CoV-2 with IC50 values of 5.76 and 6.56 μM, respectively. Notably,
both D-peptides neutralized with a similar potency the infection of
two variants of concern: B.1.1.7 and B.1.351 in vitro. These potent D-peptide inhibitors are promising lead candidates
for developing SARS-CoV-2 prophylactic or therapeutic treatments.