New glucosamine-based TLR4 agonists: design, synthesis, mechanism of action, and in vivo activity as vaccine adjuvants

20 p.-15 fig.-1 graph. abst.We disclose here a panel of small-molecule TLR4 agonists (the FP20 series) whose structure is derived from previously developed TLR4 ligands (FP18 series). The new molecules have increased chemical stability and a shorter, more efficient, and scalable synthesis. The FP20 series showed selective activity as TLR4 agonists with a potency similar to FP18. Interestingly, despite the chemical similarity with the FP18 series, FP20 showed a different mechanism of action and immunofluorescence microscopy showed no NF-κB nor p-IRF-3 nuclear translocation but rather MAPK and NLRP3-dependent inflammasome activation. The computational studies related a 3D shape of FP20 series with agonist binding properties inside the MD-2 pocket. FP20 displayed a CMC value lower than 5 μM in water, and small unilamellar vesicle (SUV) formation was observed in the biological activity concentration range. FP20 showed no toxicity in mouse vaccination experiments with OVA antigen and induced IgG production, thus indicating a promising adjuvant activity.The authors acknowledge the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie, project BactiVax (www.bactivax.eu) grant agreement no. 860325; the consortium CINMPIS; the project of excellence CHRONOS, CHRonical multifactorial disorders explored by NOvel integrated Strategies of the Department of Biotechnology and Biosciences; the Agencia Estatal de Investigacion (Spain) for project PID2021-126130OB-I00 (N.G.A.A.), PID2020-113588RB-I00 (S.M.-S.), PRE2018-086249 (A.M.-R), PRE2021-097247 (M.M.-T.); and project FEDER MINECO, the EM-platform at the CIC bioGUNE for support in cryo-EM imaging. J.J.-B. also thanks funding by CIBERES, an initiative of Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Perkin-Elmer Italia is also acknowledged for providing the cell imaging reagents.Peer reviewe

Determination of energy level alignment at metal/molecule interfaces by in-device electrical spectroscopy

The energetics of metal/molecular semiconductor interfaces plays a fundamental role in organic electronics, determining the performance of very diverse devices. So far, information about the energy level alignment has been most commonly gained by spectroscopy techniques that typically require experimental conditions far from the real device operation. Here we demonstrate that a simple three-terminal device allows the acquisition of spectroscopic information about the metal/molecule energy alignment in real operative condition. As a proof of principle, we employ the proposed device to measure the energy barrier height between different clean metals and C60 molecules and we recover typical results from photoemission spectroscopy. The device is designed to inject a hot electron current directly into the molecular level devoted to charge transport, disentangling the contributions of both the interface and the bulk to the device total resistance, with important implications for spintronics and low-temperature physics.Fil: Gobbi, M.. CIC nanoGUNE; España. Université de Strasbourg; FranciaFil: Pietrobon, L.. CIC nanoGUNE; EspañaFil: Atxabal, A.. CIC nanoGUNE; EspañaFil: Bedoya Pinto, A.. CIC nanoGUNE; EspañaFil: Sun, X.. CIC nanoGUNE; EspañaFil: Golmar, Federico. CIC nanoGUNE; España. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Llopis, R.. CIC nanoGUNE; EspañaFil: Casanova, F.. CIC nanoGUNE; España. Fundación Vasca para la Ciencia; EspañaFil: Hueso, L. E.. CIC nanoGUNE; España. Fundación Vasca para la Ciencia; Españ

Recent advances in the application of NMR methodologies to analyze the conformation, dynamics, and interactions of saccharides

25 p.-7 fig. Carbohydrate Chemistry: Chemical and Biological Approaches.Volume 44. Editors: Amélia Pilar Rauter, Thisbe K Lindhorst, Yves QueneauThis chapter is dedicated to the presentation of different examples of the application of solution NMR to the study of conformation, dynamics of sugar molecules (oligo and polysaccharides, glycopeptides and glycomimetics) including the investigation of glycanrelated molecular recognition events. It is not our intention to be exhaustive, rather to highlight diverse examples since 2016. They are presented depending on the chemical nature of the saccharide molecule, and on the different methodologies that can be employed.We thank MINECO (Spain, Projects) and the European Union (Project RECGLYCANMR and BACTIVAX) for financial support. AF also thanksMINECO for Juan de la Cierva contract.Peer reviewe