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Computational Design of Potent D-Peptide Inhibitors of SARS-CoV-2.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Oct 28; Vol. 64 (20), pp. 14955-14967. Date of Electronic Publication: 2021 Oct 08. - Publication Year :
- 2021
-
Abstract
- 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 <subscript>50</subscript> 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.
- Subjects :
- Humans
Vero Cells
Chlorocebus aethiops
Animals
COVID-19 Drug Treatment
Molecular Docking Simulation
Protein Binding
SARS-CoV-2 drug effects
Antiviral Agents pharmacology
Antiviral Agents chemistry
Antiviral Agents chemical synthesis
Spike Glycoprotein, Coronavirus antagonists & inhibitors
Spike Glycoprotein, Coronavirus metabolism
Angiotensin-Converting Enzyme 2 metabolism
Angiotensin-Converting Enzyme 2 antagonists & inhibitors
Peptides pharmacology
Peptides chemistry
Peptides chemical synthesis
Drug Design
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34624194
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00655