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The development of compounds with strong affinity for the receptor DC-SIGN is a topic of remarkable interest due to the role that this lectin plays in several pathogen infection processes and in the modulation of the immune response. DC-SIGN recognizes mannosylated and fucosylated oligosaccharides in a multivalent manner. Therefore, multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. We have previously demonstrated that linear pseudodi- and pseudotrisaccharides are adequate ligands for DC-SIGN. In this work, we show that multivalent presentations of these glycomimetics based on polyester dendrons and dendrimers lead to very potent inhibitors (in the nanomolar range) of cell infection by Ebola pseudotyped viral particles by blocking DC-SIGN receptor. Furthermore, SPR model experiments confirm that the described multivalent glycomimetic compounds compete in a very efficient manner with polymannosylated ligands for binding to DC-SIGN., We would like to acknowledge the financial support by the MICINN of Spain CTQ2008-01694, the EU RTN CARMUSYS (PITN-GA-2008-213592), Comune di Milano (Convenzione 55/2008), Sidaction – Ensemble contre le Sida, Fundación Mutua Madrileña (FMM2007-700) and the European FEDER funds. The expression plasmid for the glycoprotein of the Zaire strain of Ebola virus was kindly provided by Dr. A. Sanchez, Centers for Disease Control and Prevention, Atlanta, GA.

[EN] The present invention finds application in the field of medicine and, in particular, it relates to new compounds for the treatment and/or prevention of HIV; Ebola, Dengue, Hepatitis C, SARS or tuberculosis infections., [FR] La présente invention concerne le domaine de la médecine et, notamment, de nouveaux composés pour le traitement et/ou la prévention d'infections par le VIH, le virus Ébola, la dengue, l'hépatite C, le SRAS ou la tuberculose., Universita Degli Studi Di Miilano, Consejo Superior de Investigaciones Científicas (España), Universite Joseph Fourier, A1 Solicitud de patentes con informe sobre el estado de la técnica

[EN] The present invention finds application in the field of medicine and, in particular, it relates to new compounds for the treatment and/or prevention of HIV; Ebola, Dengue, Hepatitis C, SARS or tuberculosis infections. [FR] La présente invention concerne le domaine de la médecine et, notamment, de nouveaux composés pour le traitement et/ou la prévention d'infections par le VIH, le virus Ébola, la dengue, l'hépatite C, le SRAS ou la tuberculose. Peer reviewed Universita Degli Studi Di Miilano, Consejo Superior de Investigaciones Científicas (España), Universite Joseph Fourier A1 Solicitud de patentes con informe sobre el estado de la técnica

311 pp., El objetivo principal de esta Tesis Doctoral el desarrollo de nuevos y mejores inhibidores de la infección y propagación de agentes patógenos que utilizan la proteína DC-SIGN como receptor de entrada celular. Para alcanzar dicho objetivo general se marcaron los siguientes objetivos concretos que constituyen el trabajo de la presente Tesis Doctoral: 1. Ampliar el espectro de inhibición a otros agentes de infección viral como el VIH. 2. Análisis de la interacción entre estos sistemas glicodendríticos y el receptor DC-SIGN utilizando biosensores con detección de Resonancia del Plasmón de Superficie (SPR). 3. Mejora de la actividad antiviral de los compuestos utilizando oligosacáridos de manosa más complejos (disacáridos y trisacáridos), similares a los que se encuentran en la estructura de high mannose. 4. Preparación de sistemas multivalentes de forma monodispersa por síntesis química, que faciliten la caracterización de los productos finales y la interpretación de los resultados biológicos.

31 p.-6 fig.-14 fig. supl., The cell membrane regulates the exchange of molecules and information with the external environment. However, this control barrier hinders the delivery of exogenous bioactive molecules that can be applied to correct cellular malfunctions. Therefore, the traffic of macromolecules across the cell membrane represents a great challenge for the development of the next generation of therapies and diagnostic methods. Cell‐penetrating peptides are short peptide sequences capable of delivering a broad range of biomacromolecules across the cellular membrane. However, penetrating peptides still suffer from limitations, mainly related to their lack of specificity and potential toxicity. Glycosylation has emerged as a potential promising strategy for the biological improvement of synthetic materials. In this work we have developed a new convergent strategy for the synthesis of penetrating peptides functionalized with glycan residues by an oxime bond connection. The uptake efficiency and intracellular distribution of these glycopeptides have been systematically characterized by means of flow cytometry and confocal microscopy and in zebrafish animal models. The incorporation of these glycan residues into the peptide structure influenced the internalization efficiency and cellular toxicity of the resulting glycopeptide hybrids in the different cell lines tested. The results reported herein highlight the potential of the glycosylation of penetrating peptides to modulate their activity., We acknowledge funding from the Spanish Agencia Estatal de Investigación (AEI; CTQ2014‐59646‐R, SAF2017‐89890‐R, CTQ2016‐76263‐P, CTQ2015‐64597‐C2‐2P), the Xunta de Galicia (ED431G/09, ED431C 2017/25, and 2016‐AD031), and the ERDF. I.G. received a predoctoral fellowship from the Xunta de Galicia (ED481A‐2018/116). A.R. received a predoctoral fellowship from the Fundación Segundo Gil Dávila. J.G.‐V. and L.S. acknowledge financial support received from the Xunta de Galicia (Galicia, Spain) under the Grupos de Referencia Competitiva Programme: Project GRC2014/010. J.M. received a Ramón y Cajal (RYC‐2013‐13784), an ERC Starting Investigator Grant (DYNAP‐677786) and a Young Investigator Grant from the HFSP (RGY0066/2017).