ABSTRACT
Los LYTACs (LYsosome TArgeting Chimeras) son una novedosa estrategia farmacológica basada en la degradación dirigida de proteínas extracelulares y transmembrana. Su mecanismo de acción se basa en la utilización de un receptor de membrana para internalizar a una proteína diana y promover su degradación lisosomal. Hasta la fecha, su desarrollo se ha basado en el uso de anticuerpos para la unión a la proteína diana, lo cual presenta ciertas desventajas desde el punto de vista farmacocinético y sintético. El objetivo de este trabajo es diseñar un LYTAC capaz de inducir la degradación selectiva de MMP-2 (LYTAC-MMP2), una metaloproteasa de la matriz que se encuentra sobreexpresada en diversos tipos de cáncer. LYTAC-MMP2 está formado por un ligando del receptor de manosa-6-fosfato independiente de cationes (CI- MPR) y un inhibidor selectivo de MMP2 previamente descrito. Se han empleado métodos computacionales de modelado por homología, docking y dinámica molecular para estudiar el receptor CI-MPR y su mecanismo de internalización, así como para la comparación del comportamiento dinámico libre en agua de un ligando de CI-MPR descrito en la bibliografía y el LYTAC-MMP2.(AU)
LYTACs (LYsosome TArgeting Chimeras) are a novel pharmacological strategy based on the targeted protein degradation of extracellular and transmembrane proteins. Their mechanism of action is based on the use of a membrane receptor to internalize a target protein and mediate its lysosomal degradation. To date, its development has been focused on the use of antibodies for target binding, which has certain disadvantages from the pharmacokinetic and synthetic point of view. The aim of this work is to design a LYTAC capable of inducing the selective degradation of MMP-2 (LYTAC-MMP2), a matrix metalloprotease that is overexpressed in many types of cancer. LYTAC-MMP2 consists of a cation-independent mannose-6-phosphate receptor (CI-MPR) ligand and a selective MMP-2 inhibitor developed by our research group. Computational methods of homology modelling, docking and molecular dynamics have been used to study the CI-MPR receptor and its internalization mechanism, as well as for the comparison of the dynamic behaviour in water of a CI-MPR ligand described in the literature and LYTAC-MMP2.(AU)
Subject(s)
Humans , Molecular Dynamics Simulation , Protein Transport , Metalloproteases , Mannose-6-Phosphate IsomeraseABSTRACT
Eumaeus butterflies are obligate herbivores of Zamia, the most diverse neotropical genus of cycads. Eumaeus-Zamia interactions have been characterized mainly for species distributed in North and Central America. However, larval host plant use by the southern Eumaeus clade remains largely unknown, precluding a comprehensive study of co-evolution between the genera. Here, we combine fieldwork with museum and literature surveys to expand herbivory records for Eumaeus from 21 to 38 Zamia species. We inferred a time-calibrated phylogeny of Eumaeus to test for distinct macroevolutionary scenarios of larval host plant conservatism and co-evolution. We found a remarkable coincidence between Eumaeus and Zamia diversification, with the butterfly stem group diverging at the same time as the most recent radiation of Zamia in the Miocene. Cophylogenetic reconciliation analyses show a strong cophylogenetic signal between cycads and their butterfly herbivores. Bipartite model-based approaches indicate that this is because closely related Zamia species are used by the same Eumaeus species, suggesting larval host plant resource tracking by the butterfly herbivores. Our results highlight a case of tight evolution between Eumaeus butterflies and cycads, pointing to the generality of correlated evolution and phylogenetic tracking in plant-herbivore interactions across seed plants.
ABSTRACT
Like many species, the model plant Arabidopsis thaliana exhibits multiple different life histories in natural environments. We grew mutants impaired in different signaling pathways in field experiments across the species' native European range in order to dissect the mechanisms underlying this variation. Unexpectedly, mutational loss at loci implicated in the cold requirement for flowering had little effect on life history except in late-summer cohorts. A genetically informed photothermal model of progression toward flowering explained most of the observed variation and predicted an abrupt transition from autumn flowering to spring flowering in late-summer germinants. Environmental signals control the timing of this transition, creating a critical window of acute sensitivity to genetic and climatic change that may be common for seasonally regulated life history traits.
