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

dc.rights.licenseopenen_US
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorLAPAILLERIE, Delphine
dc.contributor.authorCHARLIER, Cathy
dc.contributor.authorGUYONNET-DUPÉRAT, Véronique
dc.contributor.authorMURIGNEUX, Emilie
dc.contributor.authorFERNANDES, Henrique
dc.contributor.authorMARTINS, Fábio
dc.contributor.authorMAGALHÃES, Rita
dc.contributor.authorVIEIRA, Tatiana
dc.contributor.authorRICHETTA, Clémence
dc.contributor.authorSUBRA, Frédéric
dc.contributor.authorLEBOURGEOIS, Samuel
dc.contributor.authorCHARPENTIER, Charlotte
dc.contributor.authorDESCAMPS, Diane
dc.contributor.authorVISSEAUX, Benoît
dc.contributor.authorWEIGEL, Pierre
dc.contributor.authorFAVEREAUX, Alexandre
dc.contributor.authorBEAUVINEAU, Claire
dc.contributor.authorBURON, Frédéric
dc.contributor.authorTEULADE-FICHOU, Marie-Paule
dc.contributor.authorROUTIER, Sylvain
dc.contributor.authorGALLOIS-MONTBRUN, Sarah
dc.contributor.authorMEERTENS, Laurent
dc.contributor.authorDELELIS, Olivier
dc.contributor.authorSOUSA, Sérgio
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorPARISSI, Vincent
dc.date.accessioned2023-05-17T07:17:53Z
dc.date.available2023-05-17T07:17:53Z
dc.date.issued2022
dc.identifier.issn0066-4804en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/182173
dc.description.abstractEnSevere 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 (EC 50) between 0.1 and 0.5 mM 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.
dc.language.isoENen_US
dc.subject.enACE2
dc.subject.enCOVID-19
dc.subject.eninhibitor
dc.subject.enSARS-CoV-2
dc.subject.enspike
dc.subject.enviral entry
dc.title.enSelection of Bis-Indolyl Pyridines and Triphenylamines as New Inhibitors of SARS-CoV-2 Cellular Entry by Modulating the Spike Protein/ACE2 Interfaces
dc.typeArticle de revueen_US
dc.identifier.doi10.1128/aac.00083-22en_US
dc.subject.halChimie/Chimie thérapeutiqueen_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologie/Maladies infectieusesen_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologie/Maladies émergentesen_US
bordeaux.journalAntimicrobial Agents and Chemotherapyen_US
bordeaux.volume66en_US
bordeaux.hal.laboratoriesMFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234en_US
bordeaux.issue8en_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcehal
hal.identifierhal-03826873
hal.version1
hal.exportfalse
workflow.import.sourcehal
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Antimicrobial%20Agents%20and%20Chemotherapy&rft.date=2022&rft.volume=66&rft.issue=8&rft.eissn=0066-4804&rft.issn=0066-4804&rft.au=LAPAILLERIE,%20Delphine&CHARLIER,%20Cathy&GUYONNET-DUP%C3%89RAT,%20V%C3%A9ronique&MURIGNEUX,%20Emilie&FERNANDES,%20Henrique&rft.genre=article


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