Discovery of Novel Spike Inhibitors against SARS-CoV-2 Infection.
Int J Mol Sci
; 25(11)2024 Jun 01.
Article
in En
| MEDLINE
| ID: mdl-38892294
ABSTRACT
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC50 values of 8.8 µM, 6.7 µM, and 7.6 µM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC50 = 5.9 µM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC50 of 9.3 µM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antiviral Agents
/
Spike Glycoprotein, Coronavirus
/
Angiotensin-Converting Enzyme 2
/
SARS-CoV-2
/
COVID-19 Drug Treatment
Limits:
Humans
Language:
En
Journal:
Int J Mol Sci
Year:
2024
Type:
Article
Affiliation country:
Taiwan