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

Valiente, Pedro A.; Wen, Han; Nim, Satra; Lee, JinAh; Kim, Hyeon Ju; Kim, Jinhee; Perez-Riba, Albert; Paudel, Yagya Prasad; Hwang, Insu; Kim, Kyun-Do; Kim, Seungtaek; Kim, Philip M.

[Image: see text] 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 IC(50) 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.