Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein

Joel Ricci-Lopez (2019, [Artículo])

High-risk strains of human papillomavirus (HPV) have been identified as the etiologic agent of some anogenital tract, head, and neck cancers. Although prophylactic HPV vaccines have been approved; it is still necessary a drug-based treatment against the infection and its oncogenic effects. The E6 oncoprotein is one of the most studied therapeutic targets of HPV, it has been identified as a key factor in cell immortalization and tumor progression in HPV-positive cells. E6 can promote the degradation of p53, a tumor suppressor protein, through the interaction with the cellular ubiquitin ligase E6AP. Therefore, preventing the formation of the E6-E6AP complex is one of the main strategies to inhibit the viability and proliferation of infected cells. Herein, we propose an in silico pipeline to identify small-molecule inhibitors of the E6-E6AP interaction. Virtual screening was carried out by predicting the ADME properties of the molecules and performing ensemble-based docking simulations to E6 protein followed by binding free energy estimation through MM/PB(GB)SA methods. Finally, the top-three compounds were selected, and their stability in the E6 docked complex and their effect in the inhibition of the E6-E6AP interaction was corroborated by molecular dynamics simulation. Therefore, this pipeline and the identified molecules represent a new starting point in the development of anti-HPV drugs. © 2019 Ricci-López et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ligand, luteolin, protein E6, protein inhibitor, ubiquitin protein ligase, ubiquitin protein ligase E6AP, unclassified drug, antivirus agent, DNA binding protein, E6 protein, Human papillomavirus type 18, oncoprotein, protein binding, protein p53, TP CIENCIAS AGROPECUARIAS Y BIOTECNOLOGÍA CIENCIAS AGROPECUARIAS Y BIOTECNOLOGÍA

Functional characterization and cellular dynamics of the CDC-42 - RAC - CDC-24 module in neurospora crassa

CYNTHIA LIZZETH ARAUJO PALOMARES (2011, [Artículo])

Rho-type GTPases are key regulators that control eukaryotic cell polarity, but their role in fungal morphogenesis is only beginning to emerge. In this study, we investigate the role of the CDC-42 - RAC - CDC-24 module in Neurospora crassa. rac and cdc-42 deletion mutants are viable, but generate highly compact colonies with severe morphological defects. Double mutants carrying conditional and loss of function alleles of rac and cdc-42 are lethal, indicating that both GTPases share at least one common essential function. The defects of the GTPase mutants are phenocopied by deletion and conditional alleles of the guanine exchange factor (GEF) cdc-24, and in vitro GDP-GTP exchange assays identify CDC-24 as specific GEF for both CDC-42 and RAC. In vivo confocal microscopy shows that this module is organized as membrane-associated cap that covers the hyphal apex. However, the specific localization patterns of the three proteins are distinct, indicating different functions of RAC and CDC-42 within the hyphal tip. CDC-42 localized as confined apical membrane-associated crescent, while RAC labeled a membrane-associated ring excluding the region labeled by CDC42. The GEF CDC-24 occupied a strategic position, localizing as broad apical membrane-associated crescent and in the apical cytosol excluding the Spitzenkörper. RAC and CDC-42 also display distinct localization patterns during branch initiation and germ tube formation, with CDC-42 accumulating at the plasma membrane before RAC. Together with the distinct cellular defects of rac and cdc-42 mutants, these localizations suggest that CDC-42 is more important for polarity establishment, while the primary function of RAC may be maintaining polarity. In summary, this study identifies CDC-24 as essential regulator for RAC and CDC-42 that have common and distinct functions during polarity establishment and maintenance of cell polarity in N. crassa. © 2011 Araujo-Palomares et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

CDC24 protein, guanine nucleotide exchange factor, protein Cdc42, Rac protein, unclassified drug, cell cycle protein, fungal protein, membrane protein, multiprotein complex, protein Cdc42, Rac protein, allele, apical membrane, article, assay, cell me BIOLOGÍA Y QUÍMICA CIENCIAS DE LA VIDA MICROBIOLOGÍA MICROBIOLOGÍA

High quality diet improves lipid metabolic profile and breeding performance in the blue-footed booby, a long-lived seabird

ERICK GONZALEZ MEDINA (2018, [Artículo])

Understanding the role of diet in the physiological condition of adults during reproduction and hence its effect on reproductive performance is fundamental to understand reproductive strategies in long-lived animals. In birds, little is known about the influence of the quality of food consumed at the beginning of the reproductive period and its short-term effects on reproductive performance. To assess the role of diet in the physiological condition of female blue-footed booby, Sula nebouxii (BFBO), during reproduction we evaluated whether individual differences in diet (assessed by using δ13C and δ15N values of whole blood from female birds and muscle tissue of the principal prey species) prior to egg laying and during incubation influenced their lipid metabolic profile (measured as triglyceride levels and C:N ratio) and their reproductive performance (defined by laying date, clutch size and hatching success). Females with higher δ15N values in their blood during the courtship and incubation periods had a higher lipid metabolic profile, earlier laying date, greater clutch size (2–3 eggs) and higher hatching success. Females that laid earlier and more eggs (2–3 eggs) consumed more Pacific anchoveta (Cetengraulis mysticetus) and Pacific thread herring (Opisthonema libertate) than did other females. These two prey species also had high amounts of lipids (C:N ratio) and caloric content (Kcal/g fresh weight). The quality of food consumed by females at the beginning of reproduction affected their physiological condition, as well as their short-term reproductive performance. Our work emphasizes the importance of determining the influence of food quality during reproduction to understand the reproductive decisions and consequences in long-lived animals. © 2018 González-Medina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

nitrogen 15, triacylglycerol, lipid, animal experiment, Article, breeding, carbon nitrogen ratio, clutch size, controlled study, courtship, diet, egg laying, female, food intake, hatching, lipid metabolism, muscle tissue, nonhuman, prey, reproduction CIENCIAS FÍSICO MATEMÁTICAS Y CIENCIAS DE LA TIERRA CIENCIAS DE LA TIERRA Y DEL ESPACIO OCEANOGRAFÍA OCEANOGRAFÍA

Protein retention assessment of four levels of poultry by-product substitution of fishmeal in rainbow trout (Oncorhynchus mykiss) diets using stable isotopes of nitrogen (δ15N) as natural tracers

DANIEL BADILLO ZAPATA (2014, [Artículo])

This is second part from an experiment where the nitrogen retention of poultry by-product meal (PBM) compared to fishmeal (FM) was evaluated using traditional indices. Here a quantitative method using stable isotope ratios of nitrogen (δ15N values) as natural tracers of nitrogen incorporation into fish biomass is assessed. Juvenile rainbow trout (Oncorhynchus mykiss) were fed for 80 days on isotopically distinct diets in which 0, 33, 66 and 100% of FM as main protein source was replaced by PBM. The diets were isonitrogenous, isolipidic and similar in gross energy content. Fish in all treatments reached isotopic equilibrium by the end of the experiment. Two-source isotope mixing models that incorporated the isotopic composition of FM and PBM as well as that of formulated feeds, empirically derived trophic discrimination factors and the isotopic composition of fish that had reached isotopic equilibrium to the diets were used to obtain a quantitative estimate of the retention of each source of nitrogen. Fish fed the diets with 33 and 66% replacement of FM by PBM retained poultry by-product meal roughly in proportion to its level of inclusion in the diets, whereas no differences were detected in the protein efficiency ratio. Coupled with the similar biomass gain of fishes fed the different diets, our results support the inclusion of PBM as replacement for fishmeal in aquaculture feeds. A re-feeding experiment in which all fish were fed a diet of 100% FM for 28 days indicated isotopic turnover occurred very fast, providing further support for the potential of isotopic ratios as tracers of the retention of specific protein sources into fish tissues. Stable isotope analysis is a useful tool for studies that seek to obtain quantitative estimates of the retention of different protein sources. © 2014 Badillo et al.

nitrogen 15, nitrogen, protein intake, animal behavior, animal experiment, animal food, animal tissue, aquaculture, Article, biomass, controlled study, energy metabolism, food composition, juvenile animal, nonhuman, poultry by product meal, protein a CIENCIAS FÍSICO MATEMÁTICAS Y CIENCIAS DE LA TIERRA CIENCIAS DE LA TIERRA Y DEL ESPACIO OCEANOGRAFÍA OCEANOGRAFÍA