Combinatorial Chemistry Unit

Barcelona, Spain

Combinatorial Chemistry Unit

Barcelona, Spain
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Seelbach R.J.,AO Research Institute Davos | Seelbach R.J.,University of Barcelona | Fransen P.,Barcelona Institute for Research in Biomedicine | Fransen P.,CIBER ISCIII | And 16 more authors.
Acta Biomaterialia | Year: 2014

The controlled presentation of biofunctionality is of key importance for hydrogel applications in cell-based regenerative medicine. Here, a versatile approach was demonstrated to present clustered binding epitopes in an injectable, thermoresponsive hydrogel. Well-defined multivalent dendrimers bearing four integrin binding sequences and an azido moiety were covalently grafted to propargylamine-derived hyaluronic acid (Hyal-pa) using copper-catalyzed alkyne-azide cycloaddition (CuAAC), and then combined with pN-modified hyaluronan (Hyal-pN). The dendrimers were prepared by synthesizing a bifunctional diethylenetriamine pentaacetic acid core with azido and NHBoc oligo(ethylene glycol) aminoethyl branches, then further conjugated with solid-phase synthesized RGDS and DGRS peptides. Azido terminated pN was synthesized by reversible addition-fragmentation chain transfer polymerization and reacted to Hyal-pa via CuAAC. Nuclear magnetic resonance (NMR), high performance liquid chromatography, size exclusion chromatography and mass spectroscopy proved that the dendrimers had well-defined size and were disubstituted. NMR and atomic absorption analysis confirmed the hyaluronan was affixed with dendrimers or pN. Rheological measurements demonstrated that dendrimers do not influence the elastic or viscous moduli of thermoresponsive hyaluronan compositions at a relevant biological concentration. Finally, human mesenchymal stromal cells were encapsulated in the biomaterial and cultured for 21 days, demonstrating the faculty of this dendrimer-modified hydrogel as a molecular toolbox for tailoring the biofunctionality of thermoresponsive hyaluronan carriers for biomedical applications. © 2014 Acta Materialia Inc.

Cavalli S.,CIBER ISCIII | Cavalli S.,Barcelona Institute for Research in Biomedicine | Carbajo D.,Combinatorial Chemistry Unit | Acosta M.,CIBER ISCIII | And 12 more authors.
Chemical Communications | Year: 2012

Aniline-catalyzed oxime chemistry was employed to conjugate a γ-amino-proline-derived cell penetrating peptide to superparamagnetic iron oxide nanoparticles (SPIONs). Internalization of the novel nanoconjugate into HeLa cells was found to be remarkably higher compared to the analogous TAT-SPION conjugate. © 2012 The Royal Society of Chemistry.

Pulido D.,Combinatorial Chemistry Unit | Pulido D.,CIBER ISCIII | Albericio F.,CIBER ISCIII | Albericio F.,Barcelona Institute for Research in Biomedicine | And 3 more authors.
Organic Letters | Year: 2014

A highly versatile synthetic strategy is described to generate multimodal and multivalent platforms based on a diethylenetriaminepentaacetic (DTPA) core. Compounds with different functionalization patterns, from mono- to pentamodal, have been prepared using robust and simple chemistry. © 2014 American Chemical Society.

Roses C.,University of Girona | Carbajo D.,Combinatorial Chemistry Unit | Carbajo D.,CIBER ISCIII | Sanclimens G.,Combinatorial Chemistry Unit | And 13 more authors.
Tetrahedron | Year: 2012

In this study, we combined a cell-penetrating γ-peptide, PEG-1, with antimicrobial undecapeptides in order to provide compounds with anticancer properties against MDA-MB-231 human breast cancer cells. We demonstrated that the conjugates were more cytotoxic than Ac-PEG-1 and the parent undecapeptides. We also evaluated the toxicity of the conjugates against non-malignant cells. The peptide conjugate with the best biological profile was BP77-PEG-1, which, at 10 μM, showed a 71% growth inhibition in MDA-MB-231 cells and only a 17% inhibition in non-malignant cells. Therefore, this study suggests that PEG-1 mediated the undecapeptide delivery into cancer cells and that these conjugates are the proof-of-concept of this strategy to generate improved anticancer drugs based on peptides. © 2011 Elsevier Ltd. All rights reserved.

Vilches S.,Cellular Bioengineering | Vilches S.,CIBER ISCIII | Vergara C.,Cellular Bioengineering | Vergara C.,CIBER ISCIII | And 18 more authors.
PLoS ONE | Year: 2013

The physiological functions of PrPC remain enigmatic, but the central domain, comprising highly conserved regions of the protein may play an important role. Indeed, a large number of studies indicate that synthetic peptides containing residues 106-126 (CR) located in the central domain (CD, 95-133) of PrPC are neurotoxic. The central domain comprises two chemically distinct subdomains, the charge cluster (CC, 95-110) and a hydrophobic region (HR, 112-133). The aim of the present study was to establish the individual cytotoxicity of CC, HR and CD. Our results show that only the CD peptide is neurotoxic. Biochemical, Transmission Electron Microscopy and Atomic Force Microscopy experiments demonstrated that the CD peptide is able to activate caspase-3 and disrupt the cell membrane, leading to cell death. © 2013 Vilches et al.

Sanchez-Nieves J.,University of Alcalá | Sanchez-Nieves J.,CIBER ISCIII | Fransen P.,Barcelona Institute for Research in Biomedicine | Pulido D.,CIBER ISCIII | And 13 more authors.
European Journal of Medicinal Chemistry | Year: 2014

Here we synthesized carbosilane, generation 1 to 3, and PEG-based dendrons functionalized at the periphery with NHBoc groups and at the focal point with azide and alkyne moieties, respectively. The coupling of these two types of dendrons via click chemistry led to the formation of new hybrid dendrimers with two distinct moieties, the hydrophobic carbosilane and the hydrophilic PEG-based dendron. The protected dendrimers were transformed into cationic ammonium dendrimers. These unique amphiphilic dendrimers were studied as vectors for gene therapy against HIV in peripheral blood mononuclear cells (PBMC) and their performance was compared with that of a PEG-free carbosilane dendrimer. The presence of the PEG moiety afforded lower toxicities and evidenced a weaker interaction between dendrimers and siRNA when compared to the homodendrimer analogous. Both features, lower toxicity and lower dendriplex strength, are key properties for use of these vectors as carriers of nucleic material. © 2014 Elsevier B.V. All rights reserved.

Pastells C.,CSIC - Institute of Advanced Chemistry of Catalonia | Pastells C.,CIBER ISCIII | Acosta G.,Combinatorial Chemistry Unit | Acosta G.,CIBER ISCIII | And 10 more authors.
Analytica Chimica Acta | Year: 2015

The characteristic pentaglycyl cross-bridge of the Staphylococcus aureus peptidoglycan (PG) cell wall component is an attractive epitope to raise specific antibodies against this microorganism. Based on this approach, we report here for the first time a competitive ELISA able to detect S. aureus down to 104 CFU mL-1, without pre-enrichment on cell culture. The antibodies were raised against peptide-protein bioconjugates prepared by covalently coupling peptide haptens (PSau6 and PSau8) designed and synthesized taking into consideration the complex tridimensional structure in the PG polymer. Deglycosylation of the PG under acidic conditions has found to increase assay detectability. Assay performance has been evaluated in clinical samples such as bronchoalveolar lavage (BAL) and bronchoalveolar endotracheal aspirates (BAS) showing promising results for further implementation of this immunoassay as a daily routine diagnostic tool. Cross-reactivity studies have demonstrated that the immunoassay is specific for S. aureus. © 2015 Elsevier B.V.

Sancho A.,Barcelona Institute for Research in Biomedicine | Sancho A.,University of Barcelona | Sancho A.,CIBER ISCIII | Duran J.,Barcelona Institute for Research in Biomedicine | And 22 more authors.
PLoS ONE | Year: 2012

Human DOR/TP53INP2 displays a unique bifunctional role as a modulator of autophagy and gene transcription. However, the domains or regions of DOR that participate in those functions have not been identified. Here we have performed structure/function analyses of DOR guided by identification of conserved regions in the DOR gene family by phylogenetic reconstructions. We show that DOR is present in metazoan species. Invertebrates harbor only one gene, DOR/Tp53inp2, and in the common ancestor of vertebrates Tp53inp1 may have arisen by gene duplication. In keeping with these data, we show that human TP53INP1 regulates autophagy and that different DOR/TP53INP2 and TP53INP1 proteins display transcriptional activity. The use of molecular evolutionary information has been instrumental to determine the regions that participate in DOR functions. DOR and TP53INP1 proteins share two highly conserved regions (region 1, aa residues 28-42; region 2, 66-112 in human DOR). Mutation of conserved hydrophobic residues in region 1 of DOR (that are part of a nuclear export signal, NES) reduces transcriptional activity, and blocks nuclear exit and autophagic activity under autophagy-activated conditions. We also identify a functional and conserved LC3-interacting motif (LIR) in region 1 of DOR and TP53INP1 proteins. Mutation of conserved acidic residues in region 2 of DOR reduces transcriptional activity, impairs nuclear exit in response to autophagy activation, and disrupts autophagy. Taken together, our data reveal DOR and TP53INP1 as dual regulators of transcription and autophagy, and identify two conserved regions in the DOR family that concentrate multiple functions crucial for autophagy and transcription. © 2012 Sancho et al.

Seelbach R.J.,AO Research Institute Davos | Fransen P.,Barcelona Institute for Research in Biomedicine | Pulido D.,University of Barcelona | Pulido D.,Biomedical Research Networking Center in Bioengineering | And 11 more authors.
Macromolecular Bioscience | Year: 2015

BMP-2 and TGF-β1 released from injectable thermoresponsive hydrogels are studied in the presence and absence of branched macromolecules bearing BMP-2 or TGF-β1 affinity binding peptides. The synthesized branched macromolecules and the gelling compositions before and after loading with either BMP-2 or TGF-β1 are characterized physico-chemically and show a significantly lower amount of proteins released in the presence of the affinity binding peptide macromolecules. This study illustrates the potential of affinity binding peptide functionalized dendrimers to modulate the local delivery and availability of growth factors important for musculoskeletal regeneration therapies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PubMed | Combinatorial Chemistry Unit
Type: Journal Article | Journal: Organic letters | Year: 2014

A highly versatile synthetic strategy is described to generate multimodal and multivalent platforms based on a diethylenetriaminepentaacetic (DTPA) core. Compounds with different functionalization patterns, from mono- to pentamodal, have been prepared using robust and simple chemistry.

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