N-Phenylpyridine-3-Carboxamide and 6-Acetyl-1H-Indazole Inhibit the RNA Replication Step of the Dengue Virus Life Cycle

Sow, Aïssatou Aïcha; Pahmeier, Felix; Ayotte, Yann; Anton, Anaïs; Mazeaud, Clément; Charpentier, Tania; Angelo, Léna; Woo, Simon; Cerikan, Berati; Falzarano, Darryl; Abrahamyan, Levon; Lamarre, Alain ORCID: https://orcid.org/0000-0002-7913-871X; Labonté, Patrick ORCID: https://orcid.org/0000-0001-7262-3125; Cortese, Mirko; Bartenschlager, Ralf; Laplante, Steven ORCID: https://orcid.org/0000-0003-2835-5789 et Chatel-Chaix, Laurent ORCID: https://orcid.org/0000-0002-7390-8250 (2023). N-Phenylpyridine-3-Carboxamide and 6-Acetyl-1H-Indazole Inhibit the RNA Replication Step of the Dengue Virus Life Cycle Antimicrobial Agents and Chemotherapy , vol. 67 , nº 2. pp. 1-14. DOI: 10.1128/aac.01331-22.

Prévisualisation

PDF - Version publiée Disponible sous licence Creative Commons Attribution. Télécharger (2MB) | Prévisualisation

Résumé

Dengue virus (DENV) is a Flavivirus that causes the most prevalent arthropod-borne viral disease. Clinical manifestation of DENV infection ranges from asymptomatic to severe symptoms that can lead to death. Unfortunately, no antiviral treatments against DENV are currently available. In order to identify novel DENV inhibitors, we screened a library of 1,604 chemically diversified fragment-based compounds using DENV reporter viruses that allowed quantification of viral replication in infected cells. Following a validation screening, the two best inhibitor candidates were N-phenylpyridine-3-carboxamide (NPP3C) and 6-acetyl-1H-indazole (6A1HI). The half maximal effective concentration of NPP3C and 6A1H1 against DENV were 7.1 μM and 6.5 μM, respectively. 6A1H1 decreased infectious DENV particle production up to 1,000-fold without any cytotoxicity at the used concentrations. While 6A1HI was DENV-specific, NPP3C also inhibited the replication of other flaviviruses such as West Nile virus and Zika virus. Structure-activity relationship (SAR) studies with 151 analogues revealed key structural elements of NPP3C and 6A1HI required for their antiviral activity. Time-of-drug-addition experiments identified a postentry step as a target of these compounds. Consistently, using a DENV subgenomic replicon, we demonstrated that these compounds specifically impede the viral RNA replication step and exhibit a high genetic barrier-to-resistance. In contrast, viral RNA translation and the de novo biogenesis of DENV replication organelles were not affected. Overall, our data unveil NPP3C and 6A1H1 as novel DENV inhibitors. The information revealed by our SAR studies will help chemically optimize NPP3C and 6A1H1 in order to improve their anti-flaviviral potency and to challenge them in in vivo models.

Type de document:	Article
Informations complémentaires:	document 01331-22
Mots-clés libres:	SARS-CoV-2; West Nile virus; Zika virus; antivirals; dengue virus.
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	11 déc. 2023 15:01
Dernière modification:	11 déc. 2023 15:01
URI:	https://espace.inrs.ca/id/eprint/13480

Gestion Actions (Identification requise)

Modifier la notice