A5053865350- Organophosphorus compounds synthesis
- Carbohydrate Chemistry and Synthesis
- Biochemical and Molecular Research
- Enzyme Production and Characterization
- Phosphorus compounds and reactions
- RNA and protein synthesis mechanisms
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Enzyme Structure and Function
- Biofuel production and bioconversion
- Fungal Plant Pathogen Control
- Insect and Pesticide Research
- Microbial Natural Products and Biosynthesis
- HIV/AIDS drug development and treatment
- Glycosylation and Glycoproteins Research
- Enzyme Catalysis and Immobilization
- Cancer therapeutics and mechanisms
- Antifungal resistance and susceptibility
- Bacterial Genetics and Biotechnology
- Pneumocystis jirovecii pneumonia detection and treatment
- Synthesis and biological activity
- Synthesis and Biological Evaluation
- Chemical Reactions and Isotopes
- Pesticide Exposure and Toxicity
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
Technion – Israel Institute of Technology
2015-2025
Faculty (United Kingdom)
2014
Fischer (Germany)
2013
Rappaport Family Institute for Research in the Medical Sciences
2009
University of Michigan
2005
Yale University
2005
Hebrew University of Jerusalem
2003-2004
University of Houston
2001
Gause Institute of New Antibiotics Russian Academy of Medical Sciences
1998
Antibiotic (Bulgaria)
1990-1993
Nonsense mutations promote premature translational termination and represent the underlying cause of a large number human genetic diseases. The aminoglycoside antibiotic gentamicin has ability to allow mammalian ribosome read past false-stop signal generate full-length functional proteins. However, severe toxic side effects along with reduced suppression efficiency at subtoxic doses limit use for therapy. We describe here first systematic development novel 2 (NB54) exhibiting superior in...
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A series of new hybrid structures containing fluoroquinolone (ciprofloxacin) and aminoglycoside (neomycin) antibiotics linked via 1,2,3-triazole moiety were designed synthesized, their antibacterial activities determined against both Gram-negative Gram-positive bacteria, including resistant strains. The nature spacers in the ciprofloxacin neomycin parts greatly influenced activity. majority hybrids was significantly more potent than parent overcame most prevalent types resistance associated...
There is compelling evidence that aminoglycoside (AG) antibiotics can induce the mammalian ribosome to suppress disease-causing nonsense mutations and partially restore expression of functional proteins. However, prolonged AG treatment cause detrimental side effects in patients, including most prominently, ototoxicity. Recent mechanistic discussions have considered relative contributions mitochondrial cytoplasmic protein synthesis inhibition AG-induced We show AGs inhibit cells perturb cell...
Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order restore expression of functional protein. However, the process Nonsense-Mediated mRNA Decay (NMD), which reduces abundance mRNAs containing PTCs, frequently limits this approach. Here, we used a mouse model lysosomal storage disease mucopolysaccharidosis I-Hurler (MPS...
Abstract Translational read‐through‐inducing drugs (TRIDs) promote read‐through of nonsense mutations, placing them in the spotlight current gene‐based therapeutic research. Here, we compare for first time relative efficacies new‐generation aminoglycosides NB30, NB54 and chemical compound PTC124 on retinal toxicity efficacy a mutation USH1C gene, which encodes scaffold protein harmonin. This causes human Usher syndrome, most common form inherited deaf‐blindness. We quantify TRIDs cell...
Thirty-five percent of patients with Rett syndrome carry nonsense mutations in the MECP2 gene. We have recently shown transfected HeLa cells that readthrough gene can be achieved by treatment gentamicin and geneticin. This study was performed to test if also endogenously expressing mutant MeCP2 evaluate potentially more effective compounds. A mouse model generated carrying R168X mutation Transfected mutated fusion proteins ear fibroblasts isolated from new were treated novel aminoglycosides...
Nonsense mutations, generating premature termination codons (PTCs), account for 10% to 30% of the mutations in tumor suppressor genes. translational suppression, induced by small molecules including gentamicin and G418, has been suggested as a potential therapy counteract deleterious effects nonsense several genetic diseases cancers. We describe here that NB124, synthetic aminoglycoside derivative recently developed especially PTC strongly induces apoptosis human cells promoting high level...
Beta-D-xylosidases are hemilcellulases that hydrolyze short xylooligosaccharides into xylose units. Here, we describe the characterization and kinetic analysis of a family 43 beta-xylosidase from Geobacillus stearothermophilus T-6 (XynB3). Enzymes in this use an inverting single-displacement mechanism with two conserved carboxylic acids, general acid, base. XynB3 was most active at 65 degrees C pH 6.5, clear preference to xylose-based substrates. Products indicated is exoglycosidase cleaves...
Compelling evidence is now available that gentamicin and Geneticin (G418) can induce the mammalian ribosome to suppress disease-causing nonsense mutations partially restore expression of functional proteins. However, toxicity relative lack efficacy at subtoxic doses limit use for suppression therapy. Although G418 exhibits strongest activity, it very cytotoxic even low doses. We describe here first systematic development novel aminoglycoside (S)-11 exhibiting similar in vitro ex vivo...
Significance We established a new genetic method for rapidly activating Cre recombinase that is based on suppression of nonsense codon within by generation aminoglycosides. applied this strategy to successfully silence both enzymes responsible GABA biosynthesis in hypothalamic agouti-related peptide (AgRP) neurons control appetite and other behaviors. Inactivation signaling AgRP young adult mice resulted severe loss body weight abnormal glucose metabolism, whereas older only manifested...
α-l-Arabinofuranosidases cleave the l-arabinofuranoside side chains of different hemicelluloses and are key enzymes in complete degradation plant cell wall. The α-l-arabinofuranosidase fromGeobacillus stearothermophilus T-6, a family 51 glycoside hydrolase, was subjected to detailed mechanistic study. Aryl-α-l-arabinofuranosides with various leaving groups were synthesized used verify catalytic mechanism residues enzyme. steady-state constants resulting Brønsted plots for E175A mutant...
The α‐ L ‐arabinofuranosidase from Geobacillus stearothermophilus T‐6 (AbfA T‐6) belongs to the retaining family 51 glycoside hydrolases. conserved Glu175 was proposed be acid–base catalytic residue. AbfA exhibits residual activity towards aryl β‐ D ‐xylopyranosides. This phenomenon used examine properties of putative mutant E175A. Data kinetic experiments, pH profiles, azide rescue, and identification xylopyranosyl product provide firm support assignment as catalyst T‐6.
A library of eight new fluoroquinolone-nuclease conjugates containing a guanidinoethyl or aminoethyl auxiliary pendant on the 1,4,7-triazacyclononane (TACN) moiety was designed and synthesized to investigate their potential as catalytic antibiotics. The Cu(ii) complexes designer structures showed significant in vitro hydrolytic oxidative DNA cleavage activity good antibacterial against both Gram-negative Gram-positive bacteria. observed all Cu(ii)-TACN-ciprofloxacin strongly inhibited...
Defence against bioterrorism: Recent events have created an urgent need for therapeutic strategies to treat anthrax, infectious disease caused by the toxigenic bacterium Bacillus anthracis. A new class of aminoglycosides (see picture) are powerful inhibitors under physiological conditions anthrax lethal factor, which has a major role in disease, and function simultaneously as antibiotics B.
Purpose.: The human Usher syndrome (USH) is the most frequent cause of inherited combined deaf-blindness. USH clinically and genetically heterogeneous, assigned to three clinical types. severe type USH1, characterized by profound inner ear defects retinitis pigmentosa. Thus far, no effective treatment for ophthalmic component exists. p.R31X nonsense mutation in USH1C leads a disease causing premature termination gene translation. Here, we investigated capability novel synthetic...
New pseudotrisaccharide derivatives of aminoglycosides that exploit additional interaction on the shallow groove face decoding-site rRNA eukaryotic ribosome were designed, synthesized and biologically evaluated. Novel lead structures (6 7 with an 7'-OH), exhibiting enhanced specificity to cytoplasmic ribosome, superior nonsense mutation suppression activity than those gentamicin, discovered. The comparative benefit new leads was demonstrated in four different DNA-constructs underling genetic...
[reaction: see text] The clinically important antibiotic neomycin B was modified at position C5' ' by adding one extra sugar ring in the beta-configuration, and observed pseudo-pentasaccharides were tested against various bacterial strains, including pathogenic resistant strains. designed antibiotics show antibacterial activity superior to that of