Compuestos potenciadores de la actividad de glicosidasas mutantes

[EN] Compounds promoting the activity of mutant glycosidases having inhibitory activity for glycosidase enzymes, furthermore relating to a procedure for activation of mutant β-glycosidase (β-glucocerebrosidase) and mutant β-galactosidase in patients suffering lysosomal storage disorders through administration of said enzyme competitor inhibitor compounds, characterised by very high bonding specificity and a favourable ratio between the concentration thereof for pharmacological chaperone activity and the concentration thereof for inhibitor activity.[ES] Compuestos potenciadores de la actividad de glicosidasas mutantes, con actividad inhibidoras de enzimas glicosidasas y también se refiere a un procedimiento para la activación de ss-glucosidasa mutante (ss- glucocerebrosidasa) y ss-galactosidasa mutante en pacientes que padecen trastornos de almacenamiento lisosómico mediante la administración de dichos compuestos inhibidores competitivos de las enzimas, caracterizados por una especificidad de unión muy alta y una relación favorable entre su concentración para actividad de chaperona farmacológica y su concentración para actividad inhibidora.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Universidad Complutense de Sevilla, International University of Health and Welfare, Tottori UniversityA1 Solicitud de patentes con informe sobre el estado de la técnic

A Bicyclic 1-Deoxygalactonojirimycin Derivative as a Novel Pharmacological Chaperone for GM1 Gangliosidosis

Lysosomal β-galactosidase (β-Gal) deficiency causes a group of disorders that include neuronopathic GM1 gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of β-Gal as pharmacological chaperones (PCs) for the treatment of GM1 gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp2-iminosugar type, namely 5N,6S-(N′-butyliminomethylidene)-6-thio-1- deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant β-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human β-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N′-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 β-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ ameliorated the brain pathology of GM1 gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of β-Gal mutants.Ministerio de Ciencia e Innovación de España. SAF2010-15670 y CTQ2010-15848Junta de Andalucía. P08-FQM-0371

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Bicyclic (galacto)nojirimycin analogues as glycosidase inhibitors: Effect of structural modifications in their pharmacological chaperone potential towards β-glucocerebrosidase

A molecular-diversity-oriented approach for the preparation of bicyclic sp2-iminosugar glycomimetics related to nojirimycin and galactonojirimycin is reported. The synthetic strategy takes advantage of the ability of endocyclic pseudoamide-type atoms in five-membered cyclic iso(thio)ureas and guanidines to undergo intramolecular nucleophilic addition to the masked carbonyl group of monosaccharides. The stereochemistry of the resulting hemiaminal stereocenter is governed by the anomeric effect, with a large preference for the axial (pseudo-α) orientation. A library of compounds differing in the stereochemistry at the position equivalent to C-4 in monosaccharides (D-gluco and D-galacto), the heterocyclic core (cyclic isourea, isothiourea or guanidine) and the nature of the exocyclic nitrogen substituent (apolar, polar, linear or branched) has been thus prepared and the glycosidase inhibitory activity evaluated against commercial glycosidases. Compounds bearing lipophilic substituents behaved as potent and very selective inhibitors of β-glucosidases. They further proved to be good competitive inhibitors of the recombinant human β-glucocerebrosidase (imiglucerase) used in enzyme replacement therapy (ERT) for Gaucher disease. The potential of these compounds as pharmacological chaperones was assessed by measuring their ability to inhibit thermal-induced denaturation of the enzyme in comparison with N-nonyl-1-deoxynojirimycin (NNDNJ). The results indicated that amphiphilic sp2-iminosugars within this series are more efficient than NNDNJ at stabilizing β-glucocerebrosidase and have a strong potential in pharmacological chaperone (PC) and ERT-PC combined therapies.The Spanish Ministerio de Ciencia e Innovaci ´on (contract numbers CTQ2006-15515-CO2-01, CTQ2009-14551-C02-01, CTQ- 2010-15848, CTQ2008-01426/BQU and SAF2010-15670;cofinanced with the Fondo Europeo de Desarrollo Regional FEDER), the Fundaci´on Ram´on Areces, and the Junta de Andaluc´ıa (P08-FQM-03711) are thanked for funding. Imiglucerase was generously supplied by Genzyme Corporation.Peer reviewe

Fluorescent-tagged sp2-iminosugars with potent β-glucosidase inhibitory activity

7 páginas, 3 figuras, 1 tablaNew fluorescently-labelled sp2-iminosugars based on the 5N,6S-[N′-(4-aminobutyl)iminomethylidene]-6-thionojirimycin skeleton have been synthesized as photoprobes to monitor glycosidase binding. Dansyl, dapoxyl and coumarin fluorophores were appended to the terminal amino group at the N′-substituent by either sulfonamide or amide bridging reaction. All the conjugates behaved as strong (low micromolar to nanomolar) and selective inhibitors of β-glucosidases (almonds and bovine liver) and naringinase, in agreement with the inhibition pattern previously encountered for related iso(thio)urea-type bicyclic sp2-iminosugars. The presence of the fluorescent probe allows real-time and continuous monitoring of β-glucosidase inhibition by fluorescence resonance energy transfer (FRET), taking advantage of the intrinsic tryptophan-associated fluorescence of the protein.The Spanish Ministerio de Ciencia e Innovación (contract numbers CTQ2006-15515-CO2-01, CTQ2009-14551-C02-01 and CTQ2007-61180/PPQ; cofinanced with the Fondo Europeo de Desarrollo Regional FEDER), the Spanish Ministerio de Educación (joint Austrian-Spanish action number HU2007-0006), the Fundación Ramón Areces, and the Junta de Andalucía are thanked for funding. M.A.-M. is a FPU doctoral fellow holder.Peer reviewe

Generalized Anomeric Effect in gem-Diamines: Stereoselective Synthesis of α-N-Linked Disaccharide Mimics

4 páginas, 2 figuras, 3 esquemas.The orbital (negative hyperconjugation) contribution to the generalized anomeric effect is highly increased in bicyclic gem-diamines with a pseudoamide-type endocyclic nitrogen atom, which has been exploited for the stereoselective synthesis of configurationally stable alpha-N-linked azadisaccharide heteroanalogues of the natural disaccharides maltose and isomaltose as aglycon-sensitive inhibitors of isomaltase.This work was supported by the Spanish MEC (contract nos. CTQ2006-15515-C02-01/BQU and CTQ2007-61180/PPQ) and the Junta de Andalucía (P08-FQM-03711).Peer reviewe

Glycosidase inhibition by ring-modified castanospermine analogues: tackling enzyme selectivity by inhibitor tailoring

10 páginas, 4 figuras, 3 tablas, 2 esquemas.Synthesis of a panel of iso(thio)urea-type ring-modified castanospermine analogues bearing a freely mutarotating pseudoanomeric hydroxyl group results in tight-binding beta-glucosidase inhibitors with unusual binding signatures; the presence of an N-octyl substituent imparts a remarkable anomeric selectivity, promoting strong binding of the appropriate beta-anomer by the beta-glucosidase.The Biotechnology and Biological Sciences Research Council of the UK, the Spanish Ministerio de Ciencia e Innovación (contract numbers CTQ2006-15515-C02-01/BQU and CTQ2007-61180/PPQ) and the Junta de Andalucía are thanked for funding.Peer reviewe

Volumen 18 Número 1

Revista seriada del Instituto Humboldt en asocio con el Invemar, el Instituto de Ciencias Naturales (ICN) y el Missouri Botanical Garden, como una estrategia para ampliar la base del conocimiento de uno de los países con mayor diversidad biológica del mundo. Inicia como una publicación de listados de especies pero en 2005 amplía su espectro temático hacia la sistemática y la biogeografía. En 2010, a propósito del Año Internacional de la Biodiversidad y en pro del conocimiento, la conservación y el uso sostenible de la biodiversidad, se abre a un público más amplio, considerando trabajos inéditos de investigación sobre botánica, zoología, ecología, biología, limnología, pesquerías, conservación, manejo de recursos y uso de la biodiversidad, con buena aceptación por parte de la comunidad científica y académica. En 2013, en asocio con el SiB Colombia y con el apoyo de la GBIF, se institucionaliza la inclusión de Artículos de Datos (Data Papers) en Biota Colombiana