Development of Receptor for Advanced Glycation End Products (RAGE) ligands through target directed dynamic combinatorial chemistry: a novel class of possible antagonists.

RAGE is a transmembrane receptor of immunoglobulin family that can bind various endogenous and exogenous ligands, initiating the inflammatory downstream signaling pathways, including inflammaging. Therefore, RAGE represents an attractive drug target for age-related diseases. For the development of small-molecule RAGE antagonists, we employed protein-templated dynamic combinatorial chemistry (ptDCC) using RAGE's VC1 domain as a template, the first application of this approach in the context of RAGE. The affinities of DCC hits were validated using microscale thermophoresis. Subsequent screening against AGE2 (glyceraldehyde-modified AGE)-sRAGE (solubleRAGE) (AGE2-BSA/sRAGE) interaction using ELISA tests led to the identification of antagonists with micromolar potency. Our findings not only demonstrate the successful application of ptDCC on RAGE but also highlight its potential to address the pressing need for alternative strategies for the development of small-molecule RAGE antagonists, an area of research that has experienced a slowdown in recent years.

Activation of the P2RX7/IL-18 pathway in immune cells attenuates lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. Despite IPF being associated with a dysregulated immune response, current antifibrotics aim only at limiting fibroproliferation. Transcriptomic analyses show that the P2RX7/IL18/IFNG axis is downregulated in IPF patients and that P2RX7 has immunoregulatory functions. Using our positive modulator of P2RX7, we show that activation of the P2RX7/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an antifibrotic immune environment, with notably an enhanced IL-18-dependent IFN-γ production by lung T cells leading to a decreased production of IL-17 and TGFß. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2RX7. Hence, treatment with a small activator of P2RX7 may represent a promising strategy to help patients with lung fibrosis.

Performance comparison of chlorinated chiral stationary phases in supercritical fluid chromatography for separation of selected pyrrolidone derivatives / 药物分析学报

The effects of two chlorinated chiral stationary phases, namely, Lux Cellulose-2 and Lux i-Cellulose-5, flow-rate, percentage of co-solvent and chemical structures of the compounds on retention and reso-lution were studied within this article. In this work a backpressure of 150 bar, a temperature of 40 ℃ and 10％ of methanol as co-solvent were chosen as operating conditions. The optimum flow-rate was 2 mL/min. The percentage of co-solvent was studied between 7.5％ and 15％. We have observed that 15％ of methanol gave the best results for most of the compounds. For all the derivatives, the Lux Cellulose-2 provided better resolutions going from 1.50 to 3.59 compared with Lux i-Cellulose-5.