Péptidos catiónicos anfipáticos y su aplicación en vectores de transferencia génica

Referencia OEPM: P200001806.-- Fecha de solicitud: 20/07/2000.-- Titulares: Consejo Superior de Investigaciones Científicas (CSIC), Medplant Genetics, S.L. y Jesús Fominaya Gutiérrez.Péptidos catiónicos anfipáticos y su aplicación en vectores de transferencia génica. Estos péptidos comprenden unos restos de aminoácidos básicos, alifáticos y aromáticos, unos restos de aminoácidos básicos en los dos extremos del péptido y, preferentemente, un resto de un aminoácido aromático en la posición 3 de la secuencia del péptido. Estos péptidos tienen simultáneamente la capacidad de unir un polinucleótido y alterar membranas biológicas y son útiles para construir vectores no virales de transferencia génica, con una capacidad de condensación de material genético mejorada, y/o con una citotoxicidad reducida y/o con una eficiencia de transferencia de material genético mejorada. De aplicación en la transferencia génica con fines experimentales y terapéuticos.Peer reviewe

Evaluation of Caspase-9b and PP2Acα2 as potential biomarkers for chronic lymphocytic leukemia

International audienceBackground: Disruption of alternative splicing in apoptotic factors has been associated to chronic lymphocytic leukemia among other cancers and hematological malignancies. The proapoptotic proteins Caspase-9 and PP2Acα are functionally related in a direct interaction, which constitutes a promising target for cancer therapy. Both proteins present aberrant mRNA splicing variants that are antiapoptotic (Caspase-9b) and catalytically inactive (PP2Acα2), respectively. Results: In this work we have analyzed the relative abundance of the aberrant spliced forms Caspase-9b and PP2Acα2 in several cell lines and chronic lymphocytic leukemia patients and correlated it with several parameters of the disease. Despite 40 % of the patients presented Caspase-9b dysregulation, there was no direct association between alterations in Caspase-9b relative abundance and the parameters analyzed in medical records. More importantly, PP2Acα2 dysregulation was observed in 88 % of CLL patients and was related with advanced stages of the malignancy. Conclusions: Caspase-9b dysregulation seemed to be associated with the disease, although the differences between healthy donors and CLL patients were not statistically significant. However, PP2Acα2 dysregulation was significantly different between healthy donors and CLL patients and correlated with Binet B and C stages; therefore, we propose the use of PP2Acα2 dysregulation as a potential biomarker for advanced stages of chronic lymphocytic leukemia

Péptidos que inhiben la unión entre set y caspasa-9

[EN] The invention provides a chimeric peptide comprising a cell-penetrating peptide linked to a peptide that inhibits binding between SET protein and Caspase-9 protein, wherein the peptide that inhibits binding between SET protein and Caspase-9 protein consists of, or is derived from, a portion of Caspase-9 that binds a SET protein, or a portion of SET that binds Caspase-9 protein.[ES] La invención proporciona un péptido quimérico que comprende un péptido que penetra en las células unido a un péptido que inhibe la unión entre la proteína SET y la proteína Caspasa-9, en donde el péptido que inhibe la unión entre la proteína SET y la proteína Caspasa-9 consiste o se deriva de una porción de Caspasa-9 que se une a una proteína SET, o una porción de SET que se une a la proteína Caspasa-9.Peer reviewedUniversité Pierre et Marie Curie, Institut national de la santé et de la recherche médicale, Consejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Strategies to stabilize cell penetrating peptides for in vivo applications

24 páginas, 3 figuras, 1 tabla.In the era of biomedicines and engineered carrier systems, cell penetrating peptides (CPPs) have been established as a promising tool for therapeutic application. Likewise, other therapeutic peptides, successful in vivo application of CPPs will strongly depend on peptide stability, the bottleneck for this type of biodegradable molecules. In this review, the authors describe the current knowledge of the in vivo degradation for known CPPs and the different strategies available to provide a higher resistance to metabolic degradation while preserving cell penetration efficiency. Peptide stability can be improved by different means, either modifying the structure to make it unrecognizable to proteases, or preventing access of proteolytic enzymes by applying conformation restriction or shielding strategies.Peer reviewe

Conjunto pro-apoptótico y péptidos PP2A

[EN] The invention provide chimeric peptides comprising a chimeric peptide comprising a cell-penetrating peptide linked to a pro-apoptotic peptide, wherein the pro-apoptotic peptide is derived from, or consists of, a portion of PP2A protein that binds a SET protein or is derived from, or consists of, a portion of the SET protein that binds PP2A protein.[ES] La invención proporciona péptidos quiméricos que comprenden un péptido quimérico que comprende un péptido que penetra en las células unido a un péptido proapoptótico, en el que el péptido proapoptótico se deriva de una porción de la proteína PP2A que se une a una proteína SET o se deriva de ella de, o consiste en, una porción de la proteína SET que se une a la proteína PP2A.Peer reviewedUniversité Pierre et Marie Curie, Institut National de la Sante et de la Recherche Medicale, Consejo Superior de Investigaciones Científicas (España), Katholieke Universiteit LeuvenA1 Solicitud de patente con informe sobre el estado de la técnic

Conjunto pro-apoptótico y péptidos PP2A

[EN] The invention provide chimeric peptides comprising a chimeric peptide comprising a cell-penetrating peptide linked to a pro-apoptotic peptide, wherein the pro-apoptotic peptide is derived from, or consists of, a portion of PP2A protein that binds a SET protein or is derived from, or consists of, a portion of the SET protein that binds PP2A protein.[ES] La invención proporciona péptidos quiméricos que comprenden un péptido quimérico que comprende un péptido que penetra en las células unido a un péptido proapoptótico, en el que el péptido proapoptótico se deriva de una porción de la proteína PP2A que se une a una proteína SET o se deriva de ella de, o consiste en, una porción de la proteína SET que se une a la proteína PP2A.Peer reviewedUniversité Pierre et Marie Curie, Institut National de la Sante et de la Recherche Medicale, Consejo Superior de Investigaciones Científicas (España), Katholieke Universiteit LeuvenA1 Solicitud de patente con informe sobre el estado de la técnic

A new serotonin 2A receptor antagonist with potential benefits in Non-Alcoholic Fatty Liver Disease

Peripheral 5-hydroxytryptamine 2A receptor (5-HT2AR) could be a new pharmacological target for NASH, an evolution of NAFLD characterized by hepatic steatosis, cytoskeletal alterations, and hepatic inflammation that can arise with or without fibrosis. SJT4a is a synthetic β-carboline antagonist for 5-HT2AR developed by SJT molecular research to treat NASH. We performed a combined in silico/in vivo study on this potential drug to elucidate its activity and possible mechanism of action. The in silico protocol compares SJT4a with four known 5-HT2AR ligands with different activities (LSD, methiothepin, zotepine, risperidone). We performed molecular docking calculations, evaluation of binding energy by AI-based methods and Molecular Dynamics simulations of the five ligand-target complexes. Moreover, we used a pseudo-semantic analysis to evaluate the potential mechanism of action of SJT4a. In silico predictions and pseudo-semantic analysis suggested antagonistic activity for SJT4a. The in silico prediction was confirmed by [3H]-5HT radioligand binding together with SJT4a competition analysis in CHO-K1 cell cultures expressing 5-HT2AR. SJT4a was then tested in vivo. We investigated the effect of 8 weeks of treatment with SJT4A on metabolic parameters, liver pathology, NAFLD activity score, and fibrosis stage in male DIO-NASH C57BL/6 J mice diet-induced obesity fed with an obesogenic diet compared with DIO-NASH and LEAN-CHOW vehicles. In our tests, SJT4a showed intense activity in diminishing the most relevant hallmarks of NASH in the DIO-NASH mice model. We proposed a possible mode of action for SJT4a based on its 5-HT2AR antagonist activity

Spinophilin acts as a tumor suppressor by regulating Rb phosphorylation

The scaffold protein Spinophilin (SPN) is a regulatory subunit of phosphatase1a located at 17q21.33. This region is frequently associated with microsatellite instability and LOH containing a relatively high density of known tumor suppressor genes, including BRCA1. Several linkage studies have suggested the existence of an unknown tumor suppressor gene distal to BRCA1. Spn may be this gene but the mechanism through this gene make its contribution to cancer has not been described. In this study, we aimed to determine how loss of Spn may contribute to tumorigenesis. We explored the contribution of SPN to PP 1a-mediated Rb regulation. We found that the loss of Spn downregulated PPP 1CA and PP 1a activity, resulting in a high level of phosphorylated Rb, and increased ARF and p53 activity. However, in the absence of p53, reduced levels of SPN enhanced the tumorigenic potential of the cells. Furthermore, the ectopic expression of SPN in human tumor cells greatly reduced cell growth. Taken together, our results demonstrate that the loss of Spn induces a proliferative response by increasing Rb phosphorylation, which in turn activates p53, thereby, neutralizing the proliferative response. We suggest that Spn may be the tumor suppressor gene located at 17q21.33 acting through Rb regulation. © 2011 Landes Bioscience.This work was supported by grants from the Spanish Ministry of Science and Innovation (SAF2009-08605), Consejería de Ciencia e Innovación (CTS-6844) and Consejería de Salud (PI-0142) of the Junta de Andalucía. A.C.’s lab is also funded by a Fellowship from Fundación Oncológica FERO supported by Fundació Josep Botet. I.F. was funded by the Spanish Ministry of Science and Innovation. NotePeer Reviewe