Arrestin-centred interactions at the membrane and their conformational determinants.

More than 30 years after their discovery, arrestins are recognised multiprotein scaffolds that play essential roles in G protein-coupled receptor (GPCR) regulation and signalling. Originally named for their capacity to hinder GPCR coupling to G proteins and facilitate receptor desensitisation, arrestins have emerged as key hubs for a myriad of other functions, including receptor internalisation and scaffolding of signalling complexes. Recent structural studies have started to provide snapshots of the complexes formed by GPCRs and arrestins, supporting a wealth of biochemical data delineating the molecular determinants of such interactions. Furthermore, biophysical techniques have also provided key information with regards to the basal and active conformations of arrestins, and how these are affected upon GPCR activation. Here, we review the most recent advances on our understanding of GPCR-arrestin complexes, from structure to interactions of arrestins with the lipid bilayer and other proteins. We also present an updated view on the development of tools to study the conformational flexibility of arrestins, with the potential to provide experimental data to describe the dynamic models of arrestin activation.

Discovery of the First-in-Class Inhibitors of Hypoxia Up-Regulated Protein†1 (HYOU1) Suppressing Pathogenic Fibroblast Activation.

Fibroblasts are key regulators of inflammation, fibrosis, and cancer. Targeting their activation in these complex diseases has emerged as a novel strategy to restore tissue homeostasis. Here, we present a multidisciplinary lead discovery approach to identify and optimize small molecule inhibitors of pathogenic fibroblast activation. The study encompasses medicinal chemistry, molecular phenotyping assays, chemoproteomics, bulk RNA-sequencing analysis, target validation experiments, and chemical absorption, distribution, metabolism, excretion and toxicity (ADMET)/pharmacokinetic (PK)/in vivo evaluation. The parallel synthesis employed for the production of the new benzamide derivatives enabled us to a) pinpoint key structural elements of the scaffold that provide potent fibroblast-deactivating effects in cells, b) discriminate atoms or groups that favor or disfavor a desirable ADMET profile, and c) identify metabolic "hot spots". Furthermore, we report the discovery of the first-in-class inhibitor leads for hypoxia up-regulated protein 1 (HYOU1), a member of the heat shock protein 70 (HSP70) family often associated with cellular stress responses, particularly under hypoxic conditions. Targeting HYOU1 may therefore represent a potentially novel strategy to modulate fibroblast activation and treat chronic inflammatory and fibrotic disorders.

Two new secoiridoids from Chelonanthus alatus (Aubl) Pulle (Gentianaceae) / Dos nuevos secoiridoides de Chelonanthus alatus (Aubl) Pulle (Gentianaceae)

The species Chelananthus alatus is an herbaceous plant with known ethno botanical and medicinal properties used in control of fever, especially those produced by malaria. From dried leaves (1.11 Kg), the crude alcoholic extract was fractionated by liquid-liquid partition with different polarity solvents. From the sec-butyl alcohol soluble fraction, by successive application of chromatographic methods, four compounds type iridoid were isolated and identified by spectroscopic techniques. Compound 1 is a new secoiridoid which was identified as sweroside 7-isobutyryloxy, and it is reported here for the first time in the Gentianaceae family; the other secoiridoids which were isolated are known as vogeloside (2), dihydro-chelonanthoside (3) and sweroside (4); vogeloside was identified for the first time in this plant (C. alatus). From the isopropyl acetate extract, in conjunction with the sweroside 7- isobutyryloxy (1), chelonanthoside (5) and sweroside (4), were identified, along with the sweroside 7-isovaleryloxy-(6) as a new side chain isomeric ester of dihydrochelonanthoside (3) . This work presents the spectroscopic analysis of the new structures and some bioactivity data.

La especie Chelonanthus alatus (Gentianaceae) es una hierba de aplicaciones ethnobotánicas reconocidas en medicina tradicional, especialmente en el control de la fiebre producida por la malaria. De las hojas secas (1,11 Kg) se realizó el extracto crudo en alcohol etílico, el cual se fraccionó por partición líquido-líquido (L-L) con disolventes de diferente polaridad. De la fracción soluble en alcohol sec-butílico, se aislaron cuatro compuestos tipo seco-iridoide por aplicación sucesiva de diversos métodos cromatográficos los cuales se identificaron por técnicas espectroscópicas. El compuesto 1 es un nuevo secoiridoide identificado como de 7- isobutiriloxi-swerosido, y se reporta por primera vez en la familia Gentianaceae; los otros tres secoiridoides aislados se conocen como vogelósido (2), dihidrochelonanthosido (3) y swerósido (4); el vogelósido se identificó por primera vez en C. alatus. De la fracción soluble en acetato de isopropilo además del 7-isobutiriloxi-swerosido (1) y el swerosido se aislaron e identificaron, el chelonanthosido (5) y el isovaleriloxi-swerosido (6), el cual es un nuevo isómero del dihidrochelonanthosido. En este trabajo se presenta el análisis espectroscópico que llevó a la elucidación estructural de los compuestos novedosos y algunos datos de bioactividad.