Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.This work was supported by grants from the Government of Spain (PIE_INTRAMURAL_ LINEA 1 - 202020E079; PIE_INTRAMURAL_CSIC-202020E043). The research of CBIG consortium (constituted by IRTA-CReSA, BSC, & IrsiCaixa) is supported by Grifols pharmaceutical. We also acknowledge the crowdfunding initiative #Yomecorono (https://www.yomecorono.com). N Izquierdo-Useros has nonrestrictive funding from PharmaMar to study the antiviral effect of Plitidepsin. NJ Krogan was funded by grants from the National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, and P01AI063302); by the Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR), a collaboration between the University of California, San Francisco (UCSF), University of California, Berkley (UCB), and GlaxoSmithKline (GSK) (#133122P); by the Roddenberry Foundation, and gifts from QCRG philanthropic donors. This work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement #HR0011-19-2-0020. The views, opinions, and/or findings contained in this material are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. This research was partly funded by Center for Research for Influenza Pathogenesis and Transmission (CRIPT), a National Institute of Allergy and Infectious Diseases (NIAID) supported Center of Excellence for Influenza Research and Response (CEIRS, contract # 75N93021C00014), by DARPA grant HR0011-19-2-0020, by supplements to NIAID grants U19AI142733, U19AI135972, and DoD grant W81XWH-20-1-0270, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to A García-Sastre. S Yildiz received funding from a Swiss National Foundation Early Postdoc Mobility fellowship (P2GEP3_184202).Peer reviewe

Substrates of the MAPK Slt2: Shaping Yeast Cell Integrity

The cell wall integrity (CWI) MAPK pathway of budding yeast Saccharomyces cerevisiae is specialized in responding to cell wall damage, but ongoing research shows that it participates in many other stressful conditions, suggesting that it has functional diversity. The output of this pathway is mainly driven by the activity of the MAPK Slt2, which regulates important processes for yeast physiology such as fine-tuning of signaling through the CWI and other pathways, transcriptional activation in response to cell wall damage, cell cycle, or determination of the fate of some organelles. To this end, Slt2 precisely phosphorylates protein substrates, modulating their activity, stability, protein interaction, and subcellular localization. Here, after recapitulating the methods that have been employed in the discovery of proteins phosphorylated by Slt2, we review the bona fide substrates of this MAPK and the growing set of candidates still to be confirmed. In the context of the complexity of MAPK signaling regulation, we discuss how Slt2 determines yeast cell integrity through phosphorylation of these substrates. Increasing data from large-scale analyses and the available methodological approaches pave the road to early identification of new Slt2 substrates and functions

MicroMundo: an approach to One Health by Service-Learning integrating diverse educational levels

MicroMundo es la adaptación a Aprendizaje-Servicio (ApS) de la estrategia de crowdsourcing y ciencia ciudadana internacional Tiny Earth. Su objetivo de servicio esencial es acercar la cultura científica, la perspectiva One Health y la investigación biomédica a la sociedad, poniendo el foco en jóvenes estudiantes para fomentar la vocación por formación en Grados STEM y por la investigación. La pandemia de COVID-19 y sus consecuencias han puesto de manifiesto la urgencia de acercar la cultura científica en el ámbito de la Biomedicina y la Salud Pública a la sociedad e implicar en esta tarea a nuestros estudiantes. Pero también la pandemia ha impuesto cambios en nuestro esquema de trabajo durante este curso, lo que nos ha obligado a trabajar on-line en lugar de llevar a cabo las características actividades experimentales de aprendizaje activo en las que se fundamenta el proyecto en condiciones normales. Manteniendo los mismos objetivos, las intervenciones en los 20 Colegios e Institutos en los que hemos realizado el proyecto se han enfocado en la elaboración de materiales divulgativos e intervenciones en la comunidad por parte de los jóvenes estudiantes, de manera coordinada por nuestros estudiantes universitarios y la organización de un Simposio on-line de ámbito nacional donde se expusieron y compartieron las diversas iniciativas. La elevada participación en el Simposio, de inscripción gratuita (más de 500 inscritos) y la calidad de las 69 ponencias propuestas, la mayoría de manera conjunta por alumnos de instituto y universitarios, avala el enorme éxito de la iniciativa virtual y la consecución de objetivos. El material generado (videojuegos, entornos educativos virtuales, paisajes de aprendizaje, escape rooms, videos, campañas en Instagram o Tik Tok, blogs, etc) será muy valioso como material de apoyo en sucesivas ediciones de MicroMundo. Todo este material se irá divulgando en el portal www.esmisionposible.com las redes sociales @EsMisionPosible, gestionados por el proyecto. En resumen, consideramos que nuestro proyecto que implica tanto a estudiantes y profesores de centros educativos de Educación Secundaria y Bachillerato en la CAM a, como a profesores y estudiantes universitarios de los ámbitos de Sanidad Humana, Animal y Medioambiental de manera transversal e interfacultativa, ha afrontado con éxito el reto de adaptar el proyecto a la situación epidemiológica, reforzándolo con actividades no presenciales orientadas a consolidar una comunidad MicroMundo virtual en la que los estudiantes pueden compartir sus experiencias en la divulgación del problema de la resistencia y el fomento de la investigación para el descubrimiento de nuevos antimicrobianos.Depto. de Genética, Fisiología y MicrobiologíaDepto. de Microbiología y ParasitologíaDepto. de Sanidad AnimalFac. de Ciencias BiológicasFac. de FarmaciaFac. de VeterinariaTRUEOficina Universitaria ApS UCMsubmitte

Micromundo@ucm: research and awareness for the stealth pandemics of antibiotic resistance

Actualmente se estima que las resistencias antibióticas se cobran 1.270.000 vidas anualmente a nivel global. Es necesario contribuir desde multiples ángulos a preservar la efectividad de os antibióticos y descubrir nuevas etsrategias terapéuticas. MicroMundo es un proyecto de Aprendizaje-Servicio y Ciencia Ciudadana que pretende crear cultura científica y concienciación en cuestiones de Salud Global en los jóvenes. Se pretende que sean los más jóvenes, los estudiantes de ESO y Bachillerato, los responsables de la transmisión de ese conocimiento a la comunidad. Pero un segundo objetivo, no menos importante, es el de generar y potenciar vocaciones STEM e interés por el I+D en Biomedicina. Para conseguir estos objetivos, diversos equipos de estudiantes universitarios imparten y coordinan el proyecto en colegios e institutos de su comunidad, coordinados por sus tutores (profesores e investigadores del área de Microbiología de las Facultades de Farmacia, Medicina, Veterinaria y Biología, cubriendo los tres vértices del triángulo One Health: salud humana, animal y medioambiental). En la UCM, durante el curso 2021-22, treinta y dos equipos de han trabajado en unos treinta colegios e institutos, implicando a unos 600 estudiantes preuniversitarios en el trabajo experimental del proyecto.It is currently estimated that antibiotic resistance annually claims 1,270,000 lives globally. It is necessary to contribute from multiple angles to preserve the effectiveness of antibiotics and discover new therapeutic strategies. MicroMundo is a Service-Learning and Citizen Science project that aims to create a scientific culture and awareness of Global Health issues among young people. It is intended that the youngest, Secondary and Baccalaureate students, be responsible for the transmission of this knowledge to the community. But a second objective, no less important, is to generate and promote STEM vocations and interest in R&D in Biomedicine. To achieve these objectives, various teams of university students teach and coordinate the project in schools and institutes in their community, coordinated by their tutors (professors and researchers from the Microbiology area of ​​the Faculties of Pharmacy, Medicine, Veterinary Medicine and Biology, covering the three vertices of the One Health triangle: human, animal and environmental health). At the UCM, during the 2021-22 academic year, thirty-two teams have worked in thirty-two schools, involving some 600 pre-university students in the experimental work of the project.Depto. de Genética, Fisiología y MicrobiologíaDepto. de Microbiología y ParasitologíaDepto. de Sanidad AnimalSección Dptal. de Nutrición y Ciencia de los Alimentos (Veterinaria)Fac. de Ciencias BiológicasFac. de FarmaciaFac. de VeterinariaTRUEunpu

MicroMundo: Citizen Science for the discovery antibiotics and antimicrobial resistance awareness by Service-Learning

MicroMundo es un proyecto de Ciencia Ciudadana basado en aprendizaje activo, en el que estudiantes de ESO y Bachillerato, objeto del servicio, coordinados por equipos de estudiantes universitarios, objeto del aprendizaje, desarrollan un proyecto de investigación real. El objetivo de la investigación es el aislamiento, a partir de microorganismos de muestras de suelo, de nuevas actividades antibióticas. Los objetivos de servicio son acercar cultura científica a la sociedad en Salud Global, con foco en el problema de la resistencia a antibióticos, actuando sobre la población más joven,al tiempo que se crean en ellos vocaciones STEM y curiosidad por la I+D en Biomedicina. Durante el curso 2019-20, 150 nuevos alumnos se han incorporado al proyecto interfacultativo en la UCM, trabajando en 26 centros educativos de la Comunidad de Madrid. El confinamiento por la situación pandémica ha reforzado el interés del proyecto, pero ha obligado a pasar el entorno on-line algunas de las actuaciones previstas. No obstante, los objetivos del proyecto se han alcanzado.MicroMundo is a Citizen Science project based on active learning. Secondary and High School students, as the objects of service in a service-learning strategy, develop a real research project, coordinated by University students, the objects of learning. The goal of their research is the isolation of microorganisms from soil samples showing new antibiotic activities. The objectives of service are to bring scientific culture on Global Health, focused on antibiotic resistance awareness, to Society by acting on its youngest members. At the same time we create vocations on STEM and I+D in Biomedicine. During the 2019-20 course, 150 new students joined this interfacultative project, working in 26 Schools in Madrid. The pandemic situation forced to move some of the planned activities to the virtual environment. However, the objectives were largely accomplished.Depto. de Genética, Fisiología y MicrobiologíaDepto. de Microbiología y ParasitologíaDepto. de MedicinaDepto. de Sanidad AnimalFac. de Ciencias BiológicasFac. de FarmaciaFac. de MedicinaFac. de VeterinariaUniversidad Complutense de Madrid. Proyectos ApSunpu

Preclinical and randomized phase I studies of plitidepsin in adults hospitalized with COVID-19

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.info:eu-repo/semantics/publishedVersio