RESUMEN
Liver X receptors (LXR) are nuclear hormone receptors that play a critical role in cholesterol homeostasis. They regulate the expression of the ABCA1 gene, which mediates the efflux of cholesterol out of cells. LXR agonists are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of microbial extracts using a LXR-SPA binding assay and bioassay-guided fractionation of an active extract of a Streptomyces sp. (MA6657) led to the discovery of two new hexacyclic aromatic ketones, (-)-anthrabenzoxocinone [(-)-ABX (1)], an enantiomer of BE-24566B, and (-)-bischloroanthrabenzoxocinone [(-)-BABX (2)]. The IC50 values of LXRalpha-SPA binding are 2 microM for (-)-ABX and 10 microM for (-)-BABX. This extract was also found to inhibit type II fatty acid synthesis, and its active component, (-)-BABX, was responsible for the majority of the inhibition. All three compounds showed good Gram-positive antibacterial activity (MIC 0.5-2 microg/mL). Details of the isolation, structure elucidation, LXR ligand binding, antibacterial activity, and selectivity of inhibition of 1 and 2 are described.
Asunto(s)
Antibacterianos/aislamiento & purificación , Proteínas de Unión al ADN/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/aislamiento & purificación , Receptores Citoplasmáticos y Nucleares/metabolismo , Streptomyces/química , Antraquinonas/aislamiento & purificación , Antibacterianos/química , Antibacterianos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Concentración 50 Inhibidora , Ligandos , Receptores X del Hígado , Estructura Molecular , Receptores Nucleares Huérfanos , EstereoisomerismoRESUMEN
HIV-1 protease is one of several key enzymes required for the replication and maturation of HIV-1 virus. An almost two-decade research effort by academic and pharmaceutical institutions resulted in the successful commercialization of seven drugs that are potent inhibitors of HIV-1 protease activity and which, if used correctly, are highly effective in managing viral load. However, identification of clinical viral isolates that are resistant to these drugs indicates that this is a significant problem and that new classes of inhibitors are continually needed. Screening of microbial extracts followed by bioassay-guided isolation led to the discovery of a natural hinnuliquinone, a C(2)-symmetric bis-indolyl quinone natural product that inhibited the wild-type and a clinically resistant (A44) strain of HIV-1 protease with K(i) values of 0.97 and 1.25microM, respectively. Crystallographic analysis of the inhibitor-bound HIV-1 protease helped explain the importance of the C(2)-symmetry of hinnuliquinone for activity. Details of the isolation, biological activity, and crystallographic analysis of the inhibitor-bound protease are herein described.
Asunto(s)
Benzoquinonas/química , Benzoquinonas/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/metabolismo , Indoles/química , Indoles/metabolismo , Quinonas , Dominio Catalítico , Dimerización , Infecciones por VIH/tratamiento farmacológico , Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/enzimología , Humanos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Quercus/microbiología , Quinonas/química , Quinonas/metabolismoRESUMEN
[structure: see text] Screening of natural products extracts led to the discovery of citrafungins A and B, two new fungal metabolites of the alkylcitrate family that are inhibitors of GGTase I of various pathogenic fungal species with IC(50) values of 2.5-15 microM. These compounds exhibited antifungal activities with MIC values of 0.40-55 microM. The isolation, structure elucidation, relative and absolute stereochemistry, and biological activities of citrafungins are described.