Selection of Bis-Indolyl Pyridines and Triphenylamines as New Inhibitors of SARS-CoV-2 Cellular Entry by Modulating the Spike Protein/ACE2 Interfaces

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent that has caused the current coronavirus disease (COVID) pandemic. Viral infection relies on the viral S (spike) protein/cellular receptor ACE2 interaction. Disrupting this interaction would lead to early blockage of...

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Published in:Antimicrobial agents and chemotherapy 2022-08, Vol.66 (8), p.e0008322
Main Authors: Lapaillerie, Delphine, Charlier, Cathy, Guyonnet-Dupérat, Véronique, Murigneux, Emilie, Fernandes, Henrique S., Martins, Fábio G., Magalhães, Rita P., Vieira, Tatiana F., Richetta, Clémence, Subra, Frédéric, Lebourgeois, Samuel, Charpentier, Charlotte, Descamps, Diane, Visseaux, Benoît, Weigel, Pierre, Favereaux, Alexandre, Beauvineau, Claire, Buron, Frédéric, Teulade-Fichou, Marie-Paule, Routier, Sylvain, Gallois-Montbrun, Sarah, Meertens, Laurent, Delelis, Olivier, Sousa, Sérgio F., Parissi, Vincent
Format: Article
Language:English
Subjects:
Antiviral Agents
Life Sciences
Microbiology and Parasitology
Virology
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Summary:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent that has caused the current coronavirus disease (COVID) pandemic. Viral infection relies on the viral S (spike) protein/cellular receptor ACE2 interaction. Disrupting this interaction would lead to early blockage of viral replication. To identify chemical tools to further study these functional interfaces, 139,146 compounds from different chemical libraries were screened through an S/ACE2 in silico virtual molecular model. The best compounds were selected for further characterization using both cellular and biochemical approaches, reiterating SARS-CoV-2 entry and the S/ACE2 interaction. We report here two selected hits, bis-indolyl pyridine AB-00011778 and triphenylamine AB-00047476. Both of these compounds can block the infectivity of lentiviral vectors pseudotyped with the SARS-CoV-2 S protein as well as wild-type and circulating variant SARS-CoV-2 strains in various human cell lines, including pulmonary cells naturally susceptible to infection. AlphaLISA and biolayer interferometry confirmed a direct inhibitory effect of these drugs on the S/ACE2 association. A specific study of the AB-00011778 inhibitory properties showed that this drug inhibits viral replication with a 50% effective concentration (EC50) between 0.1 and 0.5 μM depending on the cell lines. Molecular docking calculations of the interaction parameters of the molecules within the S/ACE2 complex from both wild-type and circulating variants of the virus showed that the molecules may target multiple sites within the S/ACE2 interface. Our work indicates that AB-00011778 constitutes a good tool for modulating this interface and a strong lead compound for further therapeutic purposes.
ISSN:0066-4804
1098-6596
1098-6596
DOI:10.1128/aac.00083-22