Jumping Hurdles: Peptides Able To Overcome Biological Barriers

The cell membrane, the gastrointestinal tract, and the blood–brain barrier (BBB) are good examples of biological barriers that define and protect cells and organs. They impose different levels of restriction, but they also share common features. For instance, they all display a high lipophilic character. For this reason, hydrophilic compounds, like peptides, proteins, or nucleic acids have long been considered as unable to bypass them. However, the discovery of cell-penetrating peptides (CPPs) opened a vast field of research. Nowadays, CPPs, homing peptides, and blood–brain barrier peptide shuttles (BBB-shuttles) are good examples of peptides able to target and to cross various biological barriers. CPPs are a group of peptides able to interact with the plasma membrane and enter the cell. They display some common characteristics like positively charged residues, mainly arginines, and amphipathicity. In this field, our group has been focused on the development of proline rich CPPs and in the analysis of the importance of secondary amphipathicity in the internalization process. Proline has a privileged structure being the only amino acid with a secondary amine and a cyclic side chain. These features constrain its structure and hamper the formation of H-bonds. Taking advantage of this privileged structure, three different families of proline-rich peptides have been developed, namely, a proline-rich dendrimer, the sweet arrow peptide (SAP), and a group of foldamers based on γ-peptides. The structure and the mechanism of internalization of all of them has been evaluated and analyzed. BBB-shuttles are peptides able to cross the BBB and to carry with them compounds that cannot reach the brain parenchyma unaided. These peptides take advantage of the natural transport mechanisms present at the BBB, which are divided in active and passive transport mechanisms. On the one hand, we have developed BBB-shuttles that cross the BBB by a passive transport mechanism, like diketoperazines (DKPs), (N-MePhe)n, or (PhPro)n. On the other hand, we have investigated BBB-shuttles that utilize active transport mechanisms such as SGV, THRre, or MiniAp-4. For the development of both groups, we have explored several approaches, such as the use of peptide libraries, both chemical and phage display, or hit-to-lead optimization processes. In this Account, we describe, in chronologic order, our contribution to the development of peptides able to overcome various biological barriers and our efforts to understand the mechanisms that they display. In addition, the potential use of both CPPs and BBB-shuttles to improve the transport of promising therapeutic compounds is described

Blood-brain barrier shuttle peptides: an emerging paradigm for brain delivery

Brain delivery is one of the major challenges in drug development because of the high number of patients suffering from neural diseases and the low efficiency of the treatments available. Although the blood-brain barrier (BBB) prevents most drugs from reaching their targets, molecular vectors - known as BBB shuttles - offer great promise to safely overcome this formidable obstacle. In recent years, peptide shuttles have received growing attention because of their lower cost, reduced immunogenicity, and higher chemical versatility than traditional Trojan horse antibodies and other proteins

Virus-like glycodendrinanoparticles displaying quasi-equivalent nested polyvalency upon glycoprotein platforms potently block viral infection

Ligand polyvalency is a powerful modulator of protein–receptor interactions. Host–pathogen infection interactions are often mediated by glycan ligand–protein interactions, yet its interrogation with very high copy number ligands has been limited to heterogenous systems. Here we report that through the use of nested layers of multivalency we are able to assemble the most highly valent glycodendrimeric constructs yet seen (bearing up to 1,620 glycans). These constructs are pure and well-defined single entities that at diameters of up to 32 nm are capable of mimicking pathogens both in size and in their highly glycosylated surfaces. Through this mimicry these glyco-dendri-protein-nano-particles are capable of blocking (at picomolar concentrations) a model of the infection of T-lymphocytes and human dendritic cells by Ebola virus. The high associated polyvalency effects (β>106, β/N ~102–103) displayed on an unprecedented surface area by precise clusters suggest a general strategy for modulation of such interactions.España MICINN CTQ2008-01694España MICINN CTQ2011-2341

Protección social en España, en la Unión Europea y en el Derecho Internacional

Universidad de Sevilla VI PPIT-USLa Seguridad Social Internacional y Comunitaria. Conflictos de Leyes y Protección Social DER 2017-83040-C4-3-RCoordinación de los Sistemas de Seguridad Social en la Unión Europea e Iberoamérica DER 2015-6936

Sinopsis del Reglamento 883/2004 y del Convenio Multilateral Iberoamericano de Seguridad Social

El Reglamento 883/2004 y el Convenio Multilateral tienen por finalidad la coordinación de sistemas de Seguridad Social. Este último se caracteriza porque es el primer instrumento internacional de estas características que se adopta en el seno de la comunidad IberoamericanaRegulation 883/2004 and the Ibero-American Multilateral Convention on Social Security have both the same aim: the coordination on social security systems. The second one is the first international instrument of its kind within the Ibero-American CommunityMinisterio de Economía y Competitividad DER 2012-3211

The combined use of gold nanoparticles and infrared radiation enables cytosolic protein delivery

Cytosolic protein delivery remains elusive. The inability of most proteins to cross the cellular membrane is a huge hurdle. Here we explore the unique photothermal properties of gold nanorods (AuNRs) to trigger cytosolic delivery of proteins. Both partners, protein and AuNRs, are modified with a protease-resistant cell-penetrating peptide with nuclear targeting properties to induce internalization. Once internalised, spatiotemporal control of protein release is achieved by near-infrared laser irradiation in the safe second biological window. Importantly, catalytic amounts of AuNRs are sufficient to trigger cytosolic protein delivery. To the best of our knowledge, this is the first time that AuNRs with their maximum of absorption in the second biological window are used to deliver proteins into the intracellular space. This strategy represents a powerful tool for the cytosolic delivery of virtually any class of protein

A multi-taxa assessment of aquatic non-indigenous species introduced into Iberian freshwater and transitional waters

leading to multi-faceted ecological, economic and health impacts worldwide. The Iberian Peninsula comprises an exceptionally biodiverse Mediterranean region with a high number of threatened and endemic aquatic species, most of them strongly impacted by biological invasions. Following a structured approach that combines a systematic review of available information and expert opinion, we provide a comprehensive and updated multi-taxa inventory of aquatic NIS (fungi, macroalgae, vascular plants, invertebrates and vertebrates) in Iberian inland waters. Moreover, we assess overall patterns in the establishment status, introduction pathways, native range and temporal introduction trends of listed NIS. In addition, we discuss the legal coverage provided by both national (Spanish and Portuguese) and European NIS regulations. We inventoried 326 aquatic NIS in Iberian inland waters, including 215 established, 96 with uncertain establishment status and 15 cryptogenic taxa. Invertebrates (54.6%) and vertebrates (24.5%) were the groups with the highest number of NIS, with Arthropoda, Mollusca, and Chordata being the most represented phyla. Recorded NIS originated from diverse geographic regions, with North and South America being the most frequent. Vertebrates and vascular plants were mostly introduced through intentional pathways (i.e. release and escape), whereas invertebrates and macroalgae arrived mostly through unintentional ways (i.e. contaminant or stowaway). Most of the recorded NIS were introduced in Iberian inland waters over the second half of the 20th century, with a high number of NIS introductions being reported in the 2000s. While only 8% of the recorded NIS appear in the European Union list of Invasive Alien Species of Union concern, around 25% are listed in the Spanish and Portuguese NIS regulations. This study provides the most updated checklist of Iberian aquatic NIS, meeting the requirements set by the EU regulation and providing a baseline for the evaluation of its application. We point out the need for coordinated transnational strategies to properly tackle aquatic invasions across borders of the EU members.LIFE INVASAQUA (Especies exóticas invasoras acuáticas de sistemas de agua dulce y estuarios: sensibilización y prevención en la Península Ibérica) de la UE - LIFE17 GIE/ES/00051

El derecho del trabajo y la seguridad social en la encrucijada: retos para la disciplina laboral

Ministerio de Economía y Competitividad DER2012-32111Ministerio de Economía y Competitividad DER2015-6936