Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: A single mode of inhibition for the three HIV enzymes?

The genome of human immunodeficiency virus type 1 (HIV-1) encodes 15 distinct proteins, three of which provide essential enzymatic functions: a reverse transcriptase (RT), an integrase (IN), and a protease (PR). Since these enzymes are all homodimers, pseudohomodimers or multimers, disruption of protein-protein interactions in these retroviral enzymes may constitute an alternative way to achieve HIV-1 inhibition. A growing number. of dimerization inhibitors for these enzymes is being reported. This mini review summarizes some approaches that have been followed for the development of compounds that inhibit those three enzymes by interfering with the dimerization interfaces between the enzyme subunits. (c) 2006 Elsevier B.V. All rights reserved

TSAO compounds: The comprehensive story of a unique family of HIV-1 specific inhibitors of reverse transcriptase

Emergence of drug-resistant viral strains is one of the major milestones and the main cause for the failure of antiretroviral therapy. Combination of different anti-HIV agents has E become the standard clinical practice to keep the viral load at low or even undetectable levels and to prevent emergence of virus-drug resistance. Among the human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors, the so called nonnucleoside RT inhibitors (NNRTIs) have gained a definitive place in the treatment of HIV infections in combination with nucleoside analogue RT inhibitors (NRTIs) and HIV protease inhibitors (PIs). The virus can be markedly suppressed for a relatively long period of time when exposed to multiple drug combination therapy (highly active antiretroviral therapy, HAART). TSAO derivatives are a peculiar group of highly functionalized nucleosides that belong to the so-called nonnucleoside RT inhibitors (NNRTIs). They exert their unique selectivity for HIV-1 through a specific interaction with the p51 subunit of HIV-1 RT. They are the first small molecules that seem to interfere with the dimerization process of the enzyme. This review covers the work carried out with this unique class of specific inhibitors of HIV-1 reverse transcriptase, including structure activity relationship studies (SAR), its mechanism of action, resistance studies, model of interaction with the enzyme, etc

Identification of aspartic acid-203 in human thymidine phosphorylase as an important residue for both catalysis and non-competitive inhibition by the small molecule "crystallization chaperone" 5'-O-tritylinosine (KIN59)

Thymidine phosphorylase (TP) is a catabolic enzyme in thymidine metabolism that is frequently upregulated in many solid tumors. Elevated TP levels are associated with tumor angiogenesis, metastasis and poor prognosis. Therefore, the use of TP inhibitors might offer a promising strategy for cancer treatment. The tritylated inosine derivative 5'-O-tritylinosine (previously designated KIN59) is a noncompetitive inhibitor of TP which was previously found to be instrumental for the crystallization of human TP. A combination of computational studies including normal mode analysis, automated ligand docking and molecular dynamics simulations were performed to define a plausible binding site for 5'-O-tritylinosine on human TP. A cavity in which 5'-O-tritylinosine could fit was identified in the vicinity of the Gly405-WI419 loop at a distance of about 11 angstrom from the substrate-binding site. In the X-ray crystal structure, this pocket is characterized by an intricate hydrogen-bonding network in which Asp203 was found to play an important role to afford the loop stabilization that is required for efficient enzyme catalysis. Site-directed mutagenesis of this amino acid residue afforded a mutant enzyme with a severely compromised catalytic efficiency (V-max /K-m of mutant enzyme similar to 50-fold lower than for wild-type TP) and pronounced resistance to the inhibitory effect of 5'-O-tritylinosine. In contrast, the D203A mutant enzyme kept full sensitivity to the competitive inhibitors 6-aminothymine and 6-amino-5-bromouracil, which is in line with the kinetic properties of these inhibitors. Our findings reveal the existence of a previously unrecognized site in TP that can be targeted by small molecules to inhibit the catalytic activity of TP. (C) 2009 Elsevier Inc. All rights reserved

DNA Repair and Immune Response Pathways Are Deregulated in Melanocyte-Keratinocyte Co-cultures Derived From the Healthy Skin of Familial Melanoma Patients

Familial melanoma accounts for 10% of cases, being CDKN2A the main high-risk gene. However, the mechanisms underlying melanomagenesis in these cases remain poorly understood. Our aim was to analyze the transcriptome of melanocyte-keratinocyte co-cultures derived from healthy skin from familial melanoma patients vs. controls, to unveil pathways involved in melanoma development in at-risk individuals. Accordingly, primary melanocyte-keratinocyte co-cultures were established from the healthy skin biopsies of 16 unrelated familial melanoma patients (8 CDKN2A mutant, 8 CDKN2A wild-type) and 7 healthy controls. Whole transcriptome was captured using the SurePrint G3 Human Microarray. Transcriptome analyses included: differential gene expression, functional enrichment, and protein-protein interaction (PPI) networks. We identified a gene profile associated with familial melanoma independently of CDKN2A germline status. Functional enrichment analysis of this profile showed a downregulation of pathways related to DNA repair and immune response in familial melanoma (P less than 0.05). In addition, the PPI network analysis revealed a network that consisted of double-stranded DNA repair genes (including BRCA1, BRCA2, BRIP1, and FANCA), immune response genes, and regulation of chromosome segregation. The hub gene was BRCA1. In conclusion, the constitutive deregulation of BRCA1 pathway genes and the immune response in healthy skin could be a mechanism related to melanoma risk.The main funding of this project came from the intramural project Papel del estrés oxidativo en el desarrollo de Melanoma Familiar y otras ER comunes con predisposición al desarrollo de neoplasias cutáneas financed by Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund A way to achieve Europe ERDF. The research at the Melanoma Unit in Barcelona is partially funded by Spanish Fondo de Investigaciones Sanitarias Grants PI15/00716 and PI15/00956, of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund A way to achieve Europe ERDF; AGAUR 2017_SGR_1134 of the Catalan Government, Spain; European Commission under the 6th Framework Programme, Contract No. LSHC-CT-2006- 018702 (GenoMEL) and by the European Commission under the 7th Framework Programme, Diagnoptics; The National Cancer Institute (NCI) of the US National Institute of Health (NIH) (CA83115); a grant from Fundació La Marató de TV3 201331- 30, Catalonia, Spain; a grant from Fundación Científica de la Asociación Española Contra el Cáncer GCB15152978SOEN, Spain, and CERCA Programme/Generalitat de Catalunya. Part of the work was carried out at the Esther Koplowitz Center, Barcelona. The UC3M-CIEMAT-CIBERER-IISFJD research is mainly supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2017-86810-R) and from the Community of Madrid (AvanCell-CM S2017/BMD- 3692) which are co-funded with European Regional Development Funds (ERDF). TH was currently recipient of a PhD Fellowship at Radboud University Medical Center in the Netherlands funded by the Dutch Cancer Society (KWF) (10602)

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Joan, Isabel i Gil: l'antroponimia de Vila-real entre 1526 i 1576.

Recull i anàlisi de l’onomàstica d’una població valenciana en el període central del segle XVI, a partir d’un llibre de comptabilitat del notari Miquel Avinent. La font arxivística, per a una població estimada en uns 1.500 habitants, relaciona els noms de més de 1.200 individus, dels quals quasi una tercera part són dones. Els noms més habituals són Isabel i Joan, i el cognom amb major nombre d’individus Gil

Nucleósidos modificados para el tratamiento de infecciones por Leishmania

Nucleósidos modificados para el tratamiento de infecciones por Leishmania. Compuestos derivados de nucleósidos y su uso para el tratamiento de enfermedades infecciosas causadas por Leishmania. Además la invención se refiere a las composiciones farmacéuticas que contienen dichos compuestos.Consejo Superior de Investigaciones Científicas (España), Universidad de AlcaláA1 Solicitud de patente con informe sobre el estado de la técnic

Derivados de nucleósidos para el tratamiento de infecciones por Leishmania

Derivados de nucleósidos para el tratamiento de infecciones por Leishmania. Compuestos derivados de nucleósidos y su uso para el tratamiento de enfermedades infecciosas causadas por Leishmania. Además la invención se refiere a las composiciones farmacéuticas que contienen dichos compuestos.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad de AlcaláB1 Patente sin examen previ

Valencian Parliamentary Documents on the Internet

The purpose of this paper is to submit a project proposal regarding the publication of the Valencian Parliamentary papers in which we want to achieve three main goals: to digitize and transcribe the parliamentary sessions for later publication on the web, which will facilitate access to these texts for both the public and the scientific community; to integrate these documents into a virtual library of Parliamentary History in order to aid comparative research on the topic throughout Europe; and to foster the study of the activities of key political and economic interests, which fixed the power relations between the Aragonese monarchy and the estates of the Kingdom of Valencia (clergy, nobility, and cities)