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

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

Papel de las mutuas a la luz de su nueva ley y la reestructuración de las mismas

La Ley 35/2014, implica no sólo un cambio de denominación de las Mutuas colaboradoras con la Seguridad Social, sino el reconocimiento de un campo de actuación que va más allá de las contingencias profesionales. Ese cambio tiene una importante repercusión sobre el número de profesionales que trabajan en las Mutuas, ya que existen diferentes límites administrativos para el crecimiento del empleo en el sector público. A esto habría que añadir la destrucción de empleo, justificada por la crisis económica. Como resultado de esa realidad, se produce una importante reducción de empleo en dichas entidades. Por otro lado, la ley permite apostar por un cambio de sentido, siempre y cuando se abran nuevas líneas de acción, para lo que será necesario contar con profesionales cada vez más especializados. Lo que no está tan claro es cuáles serán sus condiciones socio laborales en relación a lo que tradicionalmente se daba en las Mutuas: niveles de empleo caracterizados por su estabilidad y calidadThe law 35/2014, involves not only a change in the title of the cooperating Mutuals, but also a wider scope of action which go further than the professional contingencies. In fact, this change has also an important effect over the number of people working in the Mutuals, since there are some administrative limits to the development of the public employment of the sector. In addition to it, we should mention the lose of jobs, justified by the economical crisis. As a result of this reality, it is produced a significant reduction in the employability of these institutions. On the other hand, the law permits a change of direction, as long as new lines of work were opened, for which will be necessary even more and better specialized staff. In this sense, what is not enough clear is which are going to be their new working conditions, since the references have traditionally been high levels of quality and stability.Ministerio de Economía y Competitividad DER2012-32111Ministerio de Economía y Competitividad DER2015-6936