35 research outputs found
A Typical Case Presentation with Spontaneous Visual Recovery in Patient Diagnosed with Leber Hereditary Optic Neuropathy Due to Rare Point Mutation in MT-ND4 Gene (m.11253T>C) and Literature Review
Leber hereditary optic neuropathy (LHON) is one of the most common inherited mitochondrial optic neuropathies, caused by mitochondrial DNA (mtDNA) mutations. Three most common mutations, namely m.11778G>A, m.14484T>G and m.3460G>A, account for the majority of LHON cases. These mutations lead to mitochondrial respiratory chain complex I damage. Typically, LHON presents at the 15–35 years of age with male predominance. LHON is associated with severe, subacute, painless bilateral vision loss and account for one of the most common causes of legal blindness in young individuals. Spontaneous visual acuity recovery is rare and has been reported in patients harbouring m.14484T>C mutation. Up to date LHON treatment is limited. Idebenone has been approved by European Medicines Agency (EMA) to treat LHON. However better understanding of disease mechanisms and ongoing treatment trials are promising and brings hope for patients. In this article we report on a patient diagnosed with LHON harbouring rare m.11253T>C mutation in MT-ND4 gene, who experienced spontaneous visual recovery. In addition, we summarise clinical presentation, diagnostic features, and treatment
Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design
The aim of rational drug design is to develop small molecules using a quantitative approach to optimize affinity. This should enhance the development of chemical compounds that would specifically, selectively, reversibly, and with high affinity interact with a target protein. It is not yet possible to develop such compounds using computational (i.e., in silico) approach and instead the lead molecules are discovered in high-throughput screening searches of large compound libraries. The main reason why in silico methods are not capable to deliver is our poor understanding of the compound structure–thermodynamics and structure–kinetics correlations. There is a need for databases of intrinsic binding parameters (e.g., the change upon binding in standard Gibbs energy (ΔGint), enthalpy (ΔHint), entropy (ΔSint), volume (ΔVintr), heat capacity (ΔCp,int), association rate (ka,int), and dissociation rate (kd,int)) between a series of closely related proteins and a chemically diverse, but pharmacophoric group-guided library of compounds together with the co-crystal structures that could help explain the structure–energetics correlations and rationally design novel compounds. Assembly of these data will facilitate attempts to provide correlations and train data for modeling of compound binding. Here, we report large datasets of the intrinsic thermodynamic and kinetic data including over 400 primary sulfonamide compound binding to a family of 12 catalytically active human carbonic anhydrases (CA). Thermodynamic parameters have been determined by the fluorescent thermal shift assay, isothermal titration calorimetry, and by the stopped-flow assay of the inhibition of enzymatic activity. Kinetic measurements were performed using surface plasmon resonance. Intrinsic thermodynamic and kinetic parameters of binding were determined by dissecting the binding-linked protonation reactions of the protein and sulfonamide. The compound structure–thermodynamics and kinetics correlations reported here helped to discover compounds that exhibited picomolar affinities, hour-long residence times, and million-fold selectivities over non-target CA isoforms. Drug-lead compounds are suggested for anticancer target CA IX and CA XII, antiglaucoma CA IV, antiobesity CA VA and CA VB, and other isoforms. Together with 85 X-ray crystallographic structures of 60 compounds bound to six CA isoforms, the database should be of help to continue developing the principles of rational target-based drug design
Effect of chitosan essential oil films on the storage-keeping quality of pork meat products
Edible films based on chitosan were prepared, with
and without basil or thyme essential oils, with the aim of
assessing their protective ability against lipid oxidation and
their antimicrobial activity. Chitosan films had good oxygenbarrier
properties, which were worsened by essential oil addition,
especially when the film equilibrium moisture content
increased. Due to the oxygen-barrier effect, all the films
effectively protected pork fat from oxidation, in comparison
to unprotected samples. In spite of the worsening of the
oxygen-barrier properties, the films with essential oils were
more effective than those of pure chitosan, which points to the
chemical action of specific antioxidant compounds of the oils.
Films were effective to control microbial growth in minced
pork meat, although the incorporation of essential oils did not
improve their antimicrobial activity. Throughout the storage,
the films led to colour changes in minced pork meat associated
with the conversion of myoglobin into metmyoglobin due to
the reduction of the oxygen availability.The authors acknowledge the financial support provided by the Universitat Politecnica de Valencia (PAID-06-09-2834), Generalitat Valenciana (GV/2010/082) and Ministerio de Educacion y Ciencia (AGL2010-20694). Author J. Bonilla is deeply grateful to Generalitat Valenciana for a Santiago Grisolia Grant.Bonilla Lagos, MJ.; Vargas, M.; Atarés Huerta, LM.; Chiralt Boix, MA. (2014). Effect of chitosan essential oil films on the storage-keeping quality of pork meat products. Food and Bioprocess Technology. 7(8):2443-2450. https://doi.org/10.1007/s11947-014-1329-3S2443245078ASTM D3985. (1995). Standard test method for oxygen gas transmission rate through plastic films and sheeting using a coulometric sensor. West Conshohocken: American Society for Testing and Materials.Atarés, L., Pérez-Masiá, R., & Chiralt, A. (2011). The role of some antioxidants in the HPMC film properties and lipid protection in coated toasted almonds. 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Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII
Design of [(2-pyrimidinylthio)acetyl]benzenesulfonamides as inhibitors of human carbonic anhydrases.
A series of [(2-pyrimidinylthio)acetyl]benzenesulfonamides were designed and synthesized. Their binding affinities as inhibitors of several recombinant human carbonic anhydrase (CA) isozymes were determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). A group of compounds containing a chlorine atom in the benzenesulfonamide ring were found to exhibit higher selectivity but lower binding affinity toward tested CAs. The crystal structures of selected compounds in complex with CA II were determined to atomic resolution. Docking studies were performed to compare the binding modes of experimentally determined crystallographic structures with computational prediction of the pyrimidine derivative binding to CA II. Several compounds bound to select CAs with single-digit nanomolar affinities and could be used as leads for inhibitor development toward a select CA isozyme
4-[N-(Substituted 4-pyrimidinyl)amino]benzenesulfonamides as inhibitors of carbonic anhydrase isozymes I, II, VII, and XIII
Intrinsic thermodynamics of sulfonamide inhibitor binding to human carbonic anhydrases I and II
Isolation and Identification of Nepetalactone Diastereomers from Commercial Samples of Nepeta cataria
Synthesis of aminocyanopyrazoles via a multi-component reaction and anti-carbonic anhydrase inhibitory activity of their sulfamide derivatives against cytosolic and transmembrane isoforms
A convenient protocol for the multicomponent reaction (MCRs) between malononitrile with an orthoester and hydrazine derivatives, under acid catalyst is described. A series of aminocyanopyrazoles 4 was prepared, isolated and characterized. These pyrazoles reacted with sodium nitrite followed by secondary amine reagent and with formic acid to lead pyrazolotriazines 6 and pyrazolopyrimidinones 7. Some of the aminopyrazoles were converted to the corresponding sulfamides by reaction with sulfamoyl chloride. The aminopyrazoles incorporating phenyl and tosyl moieties were tested as inhibitors of four carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. Many of them showed low micromolar or submicromolar inhibition of these enzymes. The corresponding sulfamides were low nanomolar CA inhibitors