Identification of new ClpC1-NTD binders for Mycobacterium tuberculosis drug development

Weinhäupl, Katharina ; Meuret, Louis ; Desrat, Sandy ; Roussy, Fanny ; Morellet, Nelly ; Beaupierre, Sandra ; Guillou, Catherine ; van Heijenoort, Carine ; Abian, Olga (Universidad de Zaragoza) ; Vega, Sonia ; Wolf, Ian ; Akopian, Tatos ; Krandor, Olga ; Rubin, Eric ; Velazquez-Campoy, Adrian (Universidad de Zaragoza) ; Gauto, Diego ; Fraga, Hugo

Resumen: MtbClpC1 is a promising drug target against tuberculosis. Recent studies have shown that several natural product antibiotics targeting the unfoldase N-terminal domain can impair MtbClpC1 function resulting in cell death. While the pharmacological properties of these natural product antibiotics prevent their use in the clinic, similar molecules binding to the same binding pockets can result in new drugs against Mtb. Here we demonstrate that we successfully used in silico screening to identify new ClpC1 N-terminal domain binders with micromolar affinity from a small compound library. In addition, we experimentally demonstrate that the new compounds bind to the same pockets used by the natural product antibiotics and inhibit ClpC1 function.

Idioma: Inglés

DOI: 10.1038/s41598-025-87535-1

Año: 2025

Publicado en: Scientific reports (Nature Publishing Group) 15, 1 (2025), 4146 [14 pp.]
ISSN: 2045-2322

Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI21-00394
Financiación: info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)