El sistema inmune bacteriano (CRISPR), una herramienta universal en la edición de genomas.

Desde hace muchos años se llevan estudiando técnicas de edición genómica que hagan posible llevar a cabo un estudio exhaustivo del genoma celular. Sin embargo, ha sido el descubrimiento del sistema CRISPR/Cas el que ha supuesto un gran avance en el mundo de la edición genómica. Originalmente, constituye el sistema inmunitario adaptativo de los organismos procariotas mediado por un grupo de repeticiones palindrómicas cortas agrupadas e interespacidas (CRISPR). Está técnica permite manipular el genoma celular de formas nunca vistas hasta el momento empleando nucleasas guiadas por RNA, como es el caso de la nucleasa Cas9; de una forma sencilla, rápida y específica pudiendo actuar sobre genes endógenos concretos de múltiples organismos diferentes que hasta el momento habían sido imposibles de manipular genéticamente. Aunque todavía quedan por definir todas sus características, el sistema CRISPR posee una amplia gama de aplicaciones, como pueden ser el diagnóstico y tratamiento de enfermedades genéticas e infecciosas, el control de plagas o en el rastreo y el control de la expresión génica empleando variantes de Cas9

Síntesis de análogos de nucleosidodifosfatohexosas con actividad antiviral potencial

Se describe la preparacion de una seria de analogos de uridinadifosfatoglucosa para su posterior evaluacion como agentes antivirales. En estos analogos el puente difosfato de cinco atomos se ha sustituido por otros puentes de tres o seis atomos que poseen, ademas, diferente estructura quimica. Para la obtencion de estos analogos de uridinadifosfatoglucosa fue necesaria la preparacion de una serie de intermedios sinteticos, derivados de glucosa y de uridina, que a su vez han exigido la creacion de nuevos metodos sinteticos y el mejoramiento de otros conocidos

Síntesis de análogos de nucleosidodifosfatohexosas con actividad antiviral potencial

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Química Orgánica I, leída el 11-07-1986.Se describe la preparacion de una seria de analogos de uridinadifosfatoglucosa para su posterior evaluacion como agentes antivirales. En estos analogos el puente difosfato de cinco atomos se ha sustituido por otros puentes de tres o seis atomos que poseen, ademas, diferente estructura quimica. Para la obtencion de estos analogos de uridinadifosfatoglucosa fue necesaria la preparacion de una serie de intermedios sinteticos, derivados de glucosa y de uridina, que a su vez han exigido la creacion de nuevos metodos sinteticos y el mejoramiento de otros conocidos.Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEProQuestpu

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

One-Pot Synthesis of Polycyclic Nucleosides with Unusual Molecular Skeletons

An R hydroxy pyrrolidine tricyclic nucleoside 3 and its spontaneous reaction with acetone is described. In this transformation highly functionalized polycyclic nucleosides with rather unusual molecular skeletons are formed in a complete regio-and stereoselective way. The reaction involves the formation of three new bonds, two of them novel carbon-carbon bonds, in a one-pot way. An enamine-iminium mechanism with participation of carbinolamine, iminium ion, and enamine intermediates is proposed as a plausible explanation for this transformation. The scope of the reaction is briefly studied concluding that the nature of the ketone (R1COR2) is critical for the initial attack of the NH to the carbonyl group.We thank Susana Ruiz for excellent technical assistance. The Spanish MEC/MCINN (project SAF 2006-12713-C02-01) and the Comunidad de Madrid (project BIPEDD-CM S-B10-0214-2006) are also acknowl- edged for financial support. The Spanish Consejo Superior de Investigaciones Cientı´ ficas is also acknowledged for a JAE-Doc contract to M.-C.B.Peer reviewe

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

Iron Oxyhydroxide-Covalent Organic Framework Nanocomposite for Efficient As(III) Removal in Water

The presence of heavy metal ions in water is an environmental issue derived mainly from industrial and mineral contamination. Metal ions such as Cd(II), Pb(II), Hg(II), or As(III) are a significant health concern worldwide because of their high toxicity, mobility, and persistence. Covalent organic frameworks (COFs) are an emerging class of crystalline organic porous materials that exhibit very interesting properties such as chemical stability, tailored design, and low density. COFs also allow the formation of composites with remarkable features because of the synergistic combination effect of their components. These characteristics make them suitable for various applications, among which water remediation is highly relevant. Herein, we present a novel nanocomposite of iron oxyhydroxide@COF (FeOOH@Tz-COF) in which lepidocrocite (γ-FeOOH) nanorods are embedded in between the COF nanoparticles favoring As(III) remediation in water. The results show a remarkable 98.4% As(III) uptake capacity in a few minutes and impressive removal efficiency in a wide pH range (pH 5−11). The chemical stability of the material in the working pH range and the capability of capturing other toxic heavy metals such as Pb(II) and Hg(II) without interference confirm the potential of FeOOH@Tz-COF as an effective adsorbent for water remediation even under harsh conditionsThis work has been supported by the Spanish MINECO (PID2019-106268GB-C32 and PCI2019-103594) and through the “María de Maeztu” Programme for Units of Excellence in R&D (CEX2018-000805-M

Optimization of a class of tryptophan dendrimers that inhibit HIV replication leads to a selective, specific, and low-nanomolar inhibitor of clinical isolates of enterovirus A71

Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range.This work has been supported by the Spanish MINECO (Project SAF2012-39760-C02-01, cofinanced by the FEDER program; Plan Nacional de Cooperación Público-Privada; and Subprograma INNPACTO IPT-2012-0213-060000, cofinanced by the FEDER program) and the Comunidad de Madrid (BIPEDD2-CM-S2010/BMD-2457). This work was also funded by EU FP7 (FP7/2007-2013) Project EUVIRNA under Grant408 Agreement 264286 by EU FP7 SILVER (Contract HEALTH-F3-2010- 260644), a grant from the Belgian Interuniversity Attraction Poles (IAP) Phase VII–P7/45 (BELVIR), and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. The Spanish MEC/MINECO is also acknowledged for a grant to E.R.-B. L.S. was funded by China Scholarship Council (CSC) Grant 201403250056. We also acknowledge Charlotte Vanderheydt for help with the processing of the antiviral data.Peer Reviewe

Tryptophan dendrimers that inhibit HIV replication, prevent virus entry and bind to the HIV envelope glycoproteins gp120 and gp41

Dendrimers containing from 9 to 18 tryptophan residues at the peryphery have been efficiently synthesized and tested against HIV replication. These compounds inhibit an early step of the replicative cycle of HIV, presumably virus entry into its target cell. Our data suggest that HIV inhibition can be achieved by the preferred interaction of the compounds herein described with glycoproteins gp120 and gp41 of the HIV envelope preventing interaction between HIV and the (co)receptors present on the host cells. The results obtained so far indicate that 9 tryptophan residues on the periphery are sufficient for efficient gp120/gp41 binding and anti-HIV activity.This work has been supported by the Spanish MINECO (project SAF2012-39760-C02, co-financed by the FEDER programme); Plan Nacional de Cooperacion Público-Privada, subprograma INNPACTO (project IPT-2012-0213-060000, co-financed by the FEDER programme), the Comunidad de Madrid (BIPEDD2-CM-S2010/BMDE2457) and by “The Centers of Excellence” of the K.U.Leuven (EF-05/ 15 and PF-10/18). The Spanish MICINN/MINECO are also acknowledged for a grant to E. Rivero-BucetaPeer Reviewe