Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease

There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus? main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.Fil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Byléhn, Fabian. University of Chicago; Estados UnidosFil: Perez Lemus, Gustavo R.. University of Chicago; Estados UnidosFil: Alvarado, Walter. University of Chicago; Estados UnidosFil: de Pablo, Juan J.. University of Chicago; Estados Unido

Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs

Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase

Recent efforts to repurpose drugs to combat COVID-19 have identified Remdesivir as a candidate. It acts on the RNA-dependent, RNA polymerase (RdRp) of the SARS-CoV-2 virus, a protein complex responsible for mediating replication of the virus's genome. However, its exact action mechanism, and that of other nucleotide analogue inhibitors, is not known. In this study, we examine at the molecular level the interaction of this drug and that of similar nucleotide analogue inhibitors, ribavirin and favilavir, by relying on atomistic molecular simulations and advanced sampling. By analyzing the binding free energies of these different drugs, it is found that all of them bind strongly at the active site. Surprisingly, however, ribavirin and favilavir do not bind the nucleotide on the complementary strand as effectively and seem to act by a different mechanism than remdesivir. Remdesivir exhibits similar binding interactions to the natural base adenine. Moreover, by analyzing remdesivir at downstream positions of the RNA, we also find that, consistent with a "delayed"termination mechanism, additional nucleotides can be incorporated after remdesivir is added, and its highly polar 1′-cyano group induces a set of conformational changes that can affect the normal RdRp complex function. By analyzing the fluctuations of residues that are altered by remdesivir binding, and comparing them to those induced by lethal point mutations, we find a possible secondary mechanism in which remdesivir destabilizes the protein complex and its interactions with the RNA strands.Fil: Byléhn, Fabian. University of Chicago; Estados UnidosFil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Perez Lemus, Gustavo R.. University of Chicago; Estados UnidosFil: Alvarado, Walter. University of Chicago; Estados UnidosFil: De Pablo, Juan J.. University of Chicago; Estados Unido

Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.Fil: Perez Lemus, Gustavo R.. University of Chicago; Estados UnidosFil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Alvarado, Walter. University of Chicago; Estados UnidosFil: Byléhn, Fabian. University of Chicago; Estados UnidosFil: de Pablo, Juan J.. University of Chicago; Estados Unido

Thermodynamics of Higher Spin Black Holes in AdS3_3

We discuss the thermodynamics of recently constructed three-dimensional higher spin black holes in SL(N,R)\times SL(N,R) Chern-Simons theory with generalized asymptotically-anti-de Sitter boundary conditions. From a holographic perspective, these bulk theories are dual to two-dimensional CFTs with W_N symmetry algebras, and the black hole solutions are dual to thermal states with higher spin chemical potentials and charges turned on. Because the notion of horizon area is not gauge-invariant in the higher spin theory, the traditional approaches to the computation of black hole entropy must be reconsidered. One possibility, explored in the recent literature, involves demanding the existence of a partition function in the CFT, and consistency with the first law of thermodynamics. This approach is not free from ambiguities, however, and in particular different definitions of energy result in different expressions for the entropy. In the present work we show that there are natural definitions of the thermodynamically conjugate variables that follow from careful examination of the variational principle, and moreover agree with those obtained via canonical methods. Building on this intuition, we derive general expressions for the higher spin black hole entropy and free energy which are written entirely in terms of the Chern-Simons connections, and are valid for both static and rotating solutions. We compare our results to other proposals in the literature, and provide a new and efficient way to determine the generalization of the Cardy formula to a situation with higher spin charges.Comment: 30 pages, PDFLaTeX; v2: typos corrected, explicit expressions for the free energy adde

Aspectos a considerar en el diseño y ejecución de espigones de baja cota : el caso del espigón de Fuentebravía

Los espigones de baja cota de coronación se han utilizado con éxito como obras necesarias para evitar la pérdida lateral de arena, en los casos en que se minimicen los efectos negativos que dichos espigones puedan causar en las playas cercanas. Han sido varios los espigones de baja cota de coronación utilizados en el litoral gaditano (Playas de Santa María del Mar en Cádiz, Regla en Chipiona, La Costilla en Rota, y Fuentebravía, en El Puerto de Santa María). Entre los factores a tener en cuenta en su diseño, destacan principalmente los siguientes aspectos (Gómez Pina, 2003): i) Técnicos, ii) Ambientales, iii) Económicos, iv) De integración en el entorno, v) Estéticos, vi) Recreacionales. Todos estos aspectos deben abordarse de una forma integral, siendo los tres últimos—aunque puedan parecer de menor importancia—cruciales a la hora de obtener la aceptación social, entre los distintos grupos que utilizan la playa

Coste de la limpieza “cotidiana” de playas

Más de 90.000 buques mercantes al año cruzan el Estrecho de Gibraltar de los que aproximadamente un 5% son petroleros. Ello, conjuntamente con la existencia de varios puertos con refinerías y polígonos industriales petroquímicos y la práctica del bunkering para aprovisionamiento de combustible, hace a la costa gaditana un punto de riesgo para la contaminación por hidrocarburos (Carmona et al., 2009). La Demarcación de Costas de Andalucía-Atlántico (DCAA), dependiente del Ministerio de Agricultura, Alimentación y Medio Ambiente, ha realizado en numerosas ocasiones la limpieza de su litoral debido a la polución producida por ese tipo de vertidos (Carmona et al., 2012), existiendo ya alguna bibliografía sobre cómo abordar la retirada de alquitrán y otros derivados similares de las playas (e.g. DGC 2005, CEPRECO 2006a, CEPRECO 2006b). Sin embargo, además de la fracción no volátil de los hidrocarburos, existe otro tipo de desechos, naturales y/o antrópicos, que llegan a nuestras playas y que, debido sobre todo al carácter turístico de nuestro litoral, deben ser recogidos. Por ley, esta limpieza corresponde a las autoridades locales. No obstante, debido a la escasez de su presupuesto, los municipios suelen atender prioritariamente a la limpieza de las playas más urbanas y de máxima utilización. Es por este motivo que, dentro de un espíritu de colaboración entre Administraciones, la DCAA, mediante su partida de conservación y mantenimiento, ha apoyado las tareas de los Ayuntamientos, reforzando la labor municipal en las playas más concurridas y limpiando aquellas que son menos visitadas ya sea por su lejanía del casco urbano o por su escasez de servicios. En esta ponencia se presentarán los medios humanos y materiales con los que se cuenta para esta tarea, aportando cifras de toneladas de basura retiradas y coste del trabajo, junto con una comparación superficial con los datos de otros organismos y alguna sugerencia de posibles mejoras de la productividad

Na+/K+-ATPase is a new interacting partner for the neuronal glycine transporter GlyT2 that downregulates its expression in vitro and in vivo

The neuronal glycine transporter GlyT2 plays a fundamental role in the glycinergic neurotransmission by recycling the neurotransmitter to the presynaptic terminal. GlyT2 is the main supplier of glycine for vesicle refilling, a process that is absolutely necessary to preserve quantal glycine content in synaptic vesicles. Alterations in GlyT2 activity modify glycinergic neurotransmission and may underlie several neuromuscular disorders, such as hyperekplexia, myoclonus, dystonia, and epilepsy. Indeed, mutations in the gene encoding GlyT2 are the main presynaptic cause of hyperekplexia in humans and produce congenital muscular dystonia type 2 (CMD2) in Belgian Blue cattle. GlyT2 function is strictly coupled to the sodium electrochemical gradient actively generated by the Na+/K+-ATPase (NKA). GlyT2 cotransports 3Na+/Cl-/glycine generating large rises of Na+ inside the presynaptic terminal that must be efficiently reduced by the NKA to preserve Na+ homeostasis. In this work, we have used high-throughput mass spectrometry to identify proteins interacting with GlyT2 in the CNS. NKA was detected as a putative candidate and through reciprocal coimmunoprecipitations and immunocytochemistry analyses the association between GlyT2 and NKA was confirmed. NKA mainly interacts with the raft-associated active pool of GlyT2, and low and high levels of the specific NKA ligand ouabain modulate the endocytosis and total expression of GlyT2 in neurons. The ouabain-mediated downregulation of GlyT2 also occurs in vivo in two different systems: zebrafish embryos and adult rats, indicating that this NKA-mediated regulatory mechanism is evolutionarily conserved and may play a relevant role in the physiological control of inhibitory glycinergic neurotransmission

Correlation between periodontal disease management and metabolic control of type 2 diabetes mellitus: a systematic literature review

Background: Diabetes and periodontal disease share common features in terms of inflammatory responses. Current scientific evidence suggests that treatment of periodontal disease might contribute to glycemic control. The objective of the study is a review of the last three years. Material and Methods: A literature search was performed in the MEDLINE (PubMed), Cochrane, and Scopus databases, for articles published between 01-01-2013 and 30-06-2015, applying the key terms “periodontal disease” AND “diabetes mellitus”. The review analyzed clinical trials of humans published in English and Spanish. Results: Thirteen clinical trials were reviewed, representing a total of 1,912 patients. Three of them had samples of 40 patients, representing a total of 1,804. Only one article achieved a Jadad score of five. Seven articles (998 patients, 52.3% total), presented a statistically significant decrease in HbA1c (p<0.05) as a result of periodontal treatment. In the six remaining articles (representing 914 patients, 47.8% of the total), the decrease in HbA1c was not significant. Patient follow-up varied between 3 to 12 months. In three articles, the follow-up was of 3, 4, and 9 months, in two 6 and 12 months. Conclusions: The majority of clinical trials showed that radicular curettage and smoothing, whether associated with antibiotics or not, can improve periodontal conditions in patients with diabetes mellitus. However, few studies suggest that this periodontal treatment improves metabolic control. However, there is no clear evidence of a relation between periodontal treatment and improved glycemic control in patients with type 2 diabetes mellitu