RESUMO
NLRP3 is a molecular sensor recognizing a wide range of danger signals. Its activation leads to the assembly of an inflammasome that allows for activation of caspase-1 and subsequent maturation of IL-1ß and IL-18, as well as cleavage of Gasdermin-d and pyroptotic cell death. The NLRP3 inflammasome has been implicated in a plethora of diseases including gout, type 2 diabetes, atherosclerosis, Alzheimer's disease, and cancer. In this publication, we describe the discovery of a novel, tricyclic, NLRP3-binding scaffold by high-throughput screening. The hit (1) could be optimized into an advanced compound NP3-562 demonstrating excellent potency in human whole blood and full inhibition of IL-1ß release in a mouse acute peritonitis model at 30 mg/kg po dose. An X-ray structure of NP3-562 bound to the NLRP3 NACHT domain revealed a unique binding mode as compared to the known sulfonylurea-based inhibitors. In addition, NP3-562 shows also a good overall development profile.
Assuntos
Diabetes Mellitus Tipo 2 , Gota , Camundongos , Animais , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Macrófagos/metabolismo , Interleucina-1beta/metabolismo , Caspase 1/metabolismoRESUMO
A media consisting of isatin-Schiff bases (isatin-3-thiosemicarbazone, isatin-3-semicarbazone, and isatin-3-phenylhydrazone) was developed to maximize the production of antibiotics Hexaene H-85 and Azalomycine B by Streptomyces hygroscopicus. The media isatin-3-thiosemicarbazone resulted in the maximum antibiotics concentration of 372 mug cm(-3) for Hexaene H-85 and 118 mug cm(-3) for Azalomycine B. The impact of modified media on soil morphology also was investigated.
RESUMO
A chemically defined media consisting of carboxymethylcellulose (CMC) was developed to maximize the production of antibiotics, hexaene H-85 and azalomycine, by Streptomyces hygroscopicus CH-7. The production of antibiotics by filamentous organisms is often dependent on the morphology and size distribution of the pellet population within the culture. By adding the polymer to the fermentation medium, the growth was changed from a single large glob to small reproducible pellets, and wall growth was diminished to a minimum. Maximum concentrations of hexaene H-85 (146.7 mg/dm(3)) and azalomycine (188.6 mg/dm(3)) were reached at 3.0% and 1.0% (w/v) CMC, respectively.
