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

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Lapaillerie, D (Author) Other; Charlier, C (Author) Other; Guyonnet Duprat, V (Author) Other; Murigneux, E (Author) Other; Fernandes, HS (Author) Other; Martins, FG (Author) Other; Magalhaes, RP (Author) Other; Vieira, TF (Author) Other; Richetta, C (Author) Other; Subra, F (Author) Other; Lebourgeois, S (Author) Other; Charpentier, C (Author) Other; Descamps, D (Author) Other; Visseaux, B (Author) Other; Weigel, P (Author) Other; Favereaux, A (Author) Other; Beauvineau, C (Author) Other; Buron, F (Author) Other; Teulade Fichou, MP (Author) Other; Routier, S (Author) Other; Gallois Montbrun, S (Author) Other; Meertens, L (Author) Other; Delelis, O (Author) Other; Sergio Filipe Sousa (Author) FCUP; Parissi, V (Author) Other

Journal

Title: Antimicrobial Agents and Chemotherapy

Vol. 66

ISSN: 0066-4804

Publisher: American Society for Microbiology

Indexing

ISI Web of Knowledge - 1 Citation

Scopus - 1 Citation

Other information

Authenticus ID: P-00W-XDH

DOI: 10.1128/aac.00083-22

Abstract (EN): 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 mu M 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 15