Mannosyl Glycodendritic Structure Inhibits DC-SIGN-Mediated Ebola Virus Infection in cis and in trans

3 páginas, 3 figuras.We have designed a glycodendritic structure, BH30sucMan, that blocks the interaction between dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and Ebola virus (EBOV) envelope. BH30sucMan inhibits DC-SIGN-mediated EBOV infection at nanomolar concentrations. BH30sucMan may counteract important steps of the infective process of EBOV and, potentially, of microorganisms shown to exploit DC-SIGN for cell entry and infection.This research was supported by DGI grant no. BQU2002-03734 to J.R. and grants FIS 01/1430 and FIPSE 3026/99 to R.D.Peer reviewe

Direito, governança, novas tecnologias e desenvolvimento econômico sustentável, globalização e transformações na ordem social e econômica

Os encontros internacionais do Conselho Nacional de Pesquisa e Pós-graduação em Direito (Conpedi) têm se consolidado como referência na disseminação de pesquisas que tratam dos novos fenômenos que envolvem o direito, com especial destaque ao Grupo de Trabalho - GT “Direito, Governança e Novas Tecnologias”, que tem se consolidado ao longo dos anos. Nessa edição as apresentações foram subdivididas em dois grandes tópicos, com dois artigos de caráter mais geral e três artigos mais específicos. Os dois artigos que envolvem temas mais gerais são intitulados “¿Por qué informática jurídica hoy (2018)?” e “Aplicabilidad, lógica y inteligéncia artificial en el derecho”; e os três artigos específicos têm como título “Relações líquidas e direito ao esquecimento: novos desafios de proteção nas relações de trabalho”, “Um quadro explicativo para implantação do processo judicial eletrônico: estudo de caso comarca de chapecó: 2014-2016” e “A internet como ator emergente ante ao direito ambiental internacional: a importância da informação e educação à proteção do meio ambiente”. O grupo de artigos que se segue tem um tema que sempre está presente de alguma forma: os dados pessoais e a sua proteção. A hiperexposição pessoal nas redes sociais, os dados pessoais sensíveis e o direito ao esquecimento na internet, inclusive advindo das relações de trabalho, foram tópicos debatidos. Enfim, os coordenadores do GT convidam a todos a lerem o teor integral dos artigos, agradecendo a participação dos autores pesquisadores dessa edição

Antiviral Activity of Self‐Assembled Glycodendro[60]fullerene Monoadducts

A series of amphiphilic glycodendro[60]fullerene monoadducts were efficiently synthesized using the CuAAC “click chemistry” approach. These glycodendrofullerenes can self‐assemble in aqueous media, in a process favoured through π‐ π interactions between the [60]fullerene moieties. This aggregation process leads to big and well‐defined compact micelles with a uniform size and spherical‐shape. The supramolecular aggregate was characterized using electronic microscopy (SEM and TEM), light scattering methods (DLS) and X‐ray methodologies (SAXS and XRD). The antiviral efficiency of these aggregates has been tested in an experimental infection assay using Ebola virus glycoprotein (EboGP) pseudotyped viral particles on Jurkat cells overexpressing DC‐SIGN and it is observed an improvement of the IC50 value with respect to other systems endowed with a higher number of carbohydrate ligands

Direito internacional e direito internacional dos direitos humanos

O VIII Encontro Internacional do CONPEDI, ocorrido entre os dias 06 e 08 de setembro de 2018, na milenar, histórica e mui acolhedora Zaragoza (Espanha), ofereceu aos seus participantes conferências, painéis e grupos de trabalho de destacada qualidade, a exemplo o Grupo de Trabalho “Direito Internacional", que reuniu um qualificadíssimo grupo de pesquisadores de todas as regiões do Brasil, com trabalhos de pertinência acadêmica e grande relevância prática. Os artigos apresentados se destacaram pelo apuro intelectual, com discussões de sensível qualidade e sobre os mais variados temas do Direito Internacional na atualidade, com destaque para a América Latina, com o envolvimento dos alunos de mestrado e doutorado, professores e profissionais, a partir de discussões respeitosas e marcadas por uma perspectiva dialógica horizontal, democrática, aberta e plural. Um rico conjunto de temáticas, a demonstrar a contemporaneidade das discussões sobre o Direito Internacional na atualidade. Estamos honrados pela Coordenação desse relevante Grupo de Trabalho (GT), com o registro da satisfação em podermos debater com todos os autores e demais participantes. Por fim, registramos os cumprimentos ao CONPEDI, pela já costumeira qualidade dos encontros, e agradecemos aos colegas da Universidade de Zaragoza (Espanha) pela acolhida que tivemos na UNIZAR - nesse relevante momento de divulgação da pesquisa científica na área do Direito. Uma cultura, culinária, história milenar e hospitalidade que conquistaram a todos nós

Topological and Multivalent Effects in Glycofullerene Oligomers as EBOLA Virus Inhibitors

The synthesis of new biocompatible antiviral materials to fight against the development of multidrug resistance is being widely explored. Due to their unique globular structure and excellent properties, [60]fullerene-based antivirals are very promising bioconjugates. In this work, fullerene derivatives with different topologies and number of glycofullerene units were synthesized by using a SPAAC copper free strategy. This procedure allowed the synthesis of compounds 1–3, containing from 20 to 40 mannose units, in a very efficient manner and in short reaction times under MW irradiation. The glycoderivatives were studied in an infection assay by a pseudotyped viral particle with Ebola virus GP1. The results obtained show that these glycofullerene oligomers are efficient inhibitors of EBOV infection with IC50s in the nanomolar range. In particular, compound 3, with four glycofullerene moieties, presents an outstanding relative inhibitory potency (RIP). We propose that this high RIP value stems from the appropriate topological features that efficiently interact with DC-SIGN

TLR7 activation in M-CSF-dependent monocyte-derived human macrophages potentiates inflammatory responses and prompts neutrophil recruitment

1 p.-4 fig.Toll-like receptor 7 (TLR7) is an endosomal Pathogen-Associated Molecular Pattern (PAMP) receptor that senses single-stranded RNA (ssRNA) and whose engagement results in the production of type I IFN and pro-inflammatory cytokines upon viral exposure. Recent genetic studies have established that a dysfunctional TLR7-initiated signaling is directly linked to the development of SARS-CoV-2-induced severe COVID-19. We previously showed that TLR7 is preferentially expressed by macrophages generated in the presence of M-CSF (M-MØ), whose MAFB-dependent transcriptome resembles pathogenic pulmonary monocyte-derived macrophage subsets in severe COVID-19. We now report that TLR7 activation in M-MØ triggers a weak MAPK, NFkB and STAT1 activation and leads to defective production of type I IFN. Nonetheless, TLR7 engagement re-programs MAFB+ M-MØ towards a distinctive transcriptional profile. Specifically, TLR7-activated M-MØ acquired the expression of genes that characterize inflammatory macrophage subsets in COVID-19 and other inflammatory diseases, including genes encoding neutrophil-attracting chemokines (CXCL1-3, CXCL5, CXCL8) reported as biomarkers for severe COVID-19. Functionally, TLR7-activated M-MØ displayed enhanced proinflammatory responses towards secondary stimulation and a robust production of neutrophil-attracting chemokines (CXCL1, CXCL5, CXCL8), which was dependent on the transcription factors MAFB and AhR. Interestingly, CXCL1 and CXCL5 release from M-MØ was also promoted by SARS-CoV-2 but not by Virus-like particles. As defective TLR7 signaling and enhanced pulmonary neutrophil/lymphocyte ratio associate with severe COVID-19, these results suggest that targeting macrophage TLR7 might be a therapeutic strategy for viral infections where monocyte-derived macrophages exhibit a pathogenic role.This research work was also funded by the European Commission – NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global)Peer reviewe

Cross neutralization of SARS‐CoV‐2 omicron subvariants after repeated doses of COVID‐19 mRNA vaccines

We have measured the humoral response to messenger RNA (mRNA) vaccines in COVID-19 naïve and convalescent individuals. Third doses of mRNA COVID-19 vaccines induced a significant increase in potency and breadth of neutralization against SARS-CoV-2 variants of concern (VoC) including Omicron subvariants BA.1, BA.2, and BA.2.12.1, that were cross-neutralized at comparable levels and less for BA.4/5. This booster effect was especially important in naïve individuals that only after the third dose achieved a level that was comparable with that of vaccinated COVID-19 convalescents except for BA.4/5. Avidity of RBD-binding antibodies was also significantly increased in naïve individuals after the third dose, indicating an association between affinity maturation and cross neutralization of VoC. These results suggest that at least three antigenic stimuli by infection or vaccination with ancestral SARS-CoV-2 sequences are required to induce high avidity cross-neutralizing antibodies. Nevertheless, the circulation of new subvariants such as BA.4/5 with partial resistance to neutralization will have to be closely monitored and eventually consider for future vaccine developments

Identification of potential inhibitors of protein-protein interaction useful to fight against Ebola and other highly pathogenic viruses

16 p.-1 fig.-1 tab.Despite the efforts to develop new treatments against Ebola virus (EBOV) there is currently no antiviral drug licensed to treat patients with Ebola virus disease (EVD). Therefore, there is still an urgent need to find new drugs to fight against EBOV. In order to do this, a virtual screening was done on the druggable interaction between the EBOV glycoprotein (GP) and the host receptor NPC1 with a subsequent selection of compounds for further validation. This screening led to the identification of new small organic molecules with potent inhibitory action against EBOV infection using lentiviral EBOV-GP-pseudotype viruses. Moreover, some of these compounds have shown their ability to interfere with the intracellular cholesterol transport receptor NPC1 using an ELISA-based assay. These preliminary results pave the way to hit to lead optimization programs that lead to successful candidates.Funding from “la Caixa” Banking Foundation under the project code HR18-00469 is acknowledged. This research was partially supported through Instituto de Salud Carlos III (FIS PI 181007 and ISCIII-COV20/01007), CSIC (201980E024 and 202020E079), Spanish Ministry of Science and Innovation (RTI2018-097305-R-I00) and the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016 and VACDIVA-SFS-12-2019-1-862874).Peer reviewe

The GSK3b-MAFB axis controls the pro-fibrotic gene profile of pathogenic monocyte-derived macrophages in severe COVID-19

1 p.-4 fig.MAF and MAFB are members of the “large MAF” transcription factor family that shape the transcriptome of antiinflammatory and pro-tumoral human macrophages. We have now determined the MAF- and MAFB-dependent gene profile of M-CSF-dependent monocyte-derived macrophages (M-MØ), and found that both factors exhibit overlapping transcriptional outcomes during monocyte-to-M-MØ differentiation, but differentially affect macrophage effector functions like production of monocyte-recruiting chemokines, T-cell activation and immunosuppression. Remarkably, MAFB was found to positively regulate the expression of the genesets that define the pathogenic monocyte-derived pulmonary macrophage subsets in COVID-19, as evidenced through siRNA-mediated silencing and analysis of MAFBoverexpressing M-MØ from a Multicentric Carpotarsal Osteolysis (MCTO) patient. MAFB silencing downregulated theexpression of genes coding for biomarkers of COVID-19 severity, and genome-wide mapping of MAFB-binding elements in M-MØ identified biomarkers of COVID-19 severity (CD163, IL10, HGF and CCL2) as direct MAFB targets. Further, and in line with the GSK3b-dependent expression of MAFB, GSK3b inhibition in M-MØ significantly boosted the expression of genes that characterize pathogenic macrophage subsets in severe COVID-19, an effect that was primarily dependent on MAFB. In addition, we have demonstrated that a large number of MAFB-dependent genes, as well as GSK3b-dependent expression of MAFB genes were modulated by SARS-Cov-2 infection on human macrophages. Globally, our results demonstrate that the GSK3b-MAFB axis controls the transcriptome of pathogenic pulmonary macrophages in COVID-19,and positively regulates the expression of biomarkers for COVID-19 severity. Thus, macrophage re-programming through modulation of GSK3 -MAFB axis has potential therapeutic strategy for COVID-19 and other inflammatory diseases.This research work was also funded by the European Commission– NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global).Peer reviewe

N′-phenylacetohydrazide derivatives as potent Ebola virus entry inhibitors with an improved pharmacokinetic profile

19 p.-6 fig.-7 tab.-1 graph. abst.Ebola virus (EBOV) is a single-strand RNA virus belonging to the Filoviridae family, which has been associated to most Ebola virus disease outbreaks to date, including the West African and the North Kivu epidemics between 2013 and 2022. This unprecedented health emergency prompted the search for effective medical countermeasures. Following up on the carbazole hit identified in our previous studies, we synthetized a new series of compounds, which demonstrated to prevent EBOV infection in cells by acting as virus entry inhibitors. The in vitro inhibitory activity was evaluated through the screening against surrogate models based on viral pseudotypes and further confirmed using replicative EBOV. Docking and molecular dynamics simulations joined to saturation transfer difference–nuclear magnetic resonance (STD–NMR) and mutagenesis experiments to elucidate the biological target of the most potent compounds. Finally, in vitro metabolic stability and in vivo pharmacokinetic studies were performed to confirm their therapeutic potential.The project leading to these results has received funding from “la Caixa” Foundation under the project code LCF/PR/HR19/52160012. This research was partially supported through ERA-NET-2021-862605. Cofounded by AEI, Spain (PCI2021-121939 (C.A.), PID2019-105237GB-I00 (A.C.), PID2021-122825OB (C.A.), and PID2021-122223OB-I00 (C.G.)), Instituto de Salud Carlos III (CIBERINFEC and FIS PI2100989), and the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016: 731868 and Project EPIC-CROWN-2 ID: 101046084). This research work was also funded by the European Commission–NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). M.M.-T holds a predoctoral FPU grant (FPU18/03493) from MICINNPeer reviewe