A5053992759- Carbohydrate Chemistry and Synthesis
- Glycosylation and Glycoproteins Research
- Cholinesterase and Neurodegenerative Diseases
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Paraoxonase enzyme and polymorphisms
- Lysosomal Storage Disorders Research
- Enzyme Structure and Function
- Chemical Reaction Mechanisms
- Cancer therapeutics and mechanisms
- Biochemical Acid Research Studies
- Cynara cardunculus studies
- Enzyme function and inhibition
- Biochemical and Molecular Research
- Alzheimer's disease research and treatments
- Enzyme Production and Characterization
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- HIV/AIDS drug development and treatment
- Chronic Lymphocytic Leukemia Research
- Inorganic and Organometallic Chemistry
- Protein Structure and Dynamics
- Synthesis of Tetrazole Derivatives
- HIV Research and Treatment
- Galectins and Cancer Biology
- Amino Acid Enzymes and Metabolism
Gilead Sciences (United States)
2023-2024
University of California, Los Angeles
2015-2018
Howard Hughes Medical Institute
2014-2018
Genomics (United Kingdom)
2015
Weizmann Institute of Science
2004-2011
Mayo Clinic
2006
Virginia Tech
2006
Technion – Israel Institute of Technology
2002
SPring-8
2002
The X-ray crystal structures were solved for complexes with Torpedo californica acetylcholinesterase of two bivalent tacrine derivative compounds in which the rings separated by 5- and 7-carbon spacers. spacer spans length active-site gorge, making sandwich interactions aromatic residues both catalytic anionic site (Trp84 Phe330) at bottom gorge peripheral near its mouth (Tyr70 Trp279). 5-carbon interacts a similar manner but shorter tether precludes interaction site. Although upper group...
Gaucher disease, the most common lysosomal storage can be treated with enzyme replacement therapy (ERT), in which defective acid-β-glucosidase (GlcCerase) is supplemented by a recombinant, active enzyme. The X-ray structures of recombinant GlcCerase produced Chinese hamster ovary cells (imiglucerase, Cerezyme®) and transgenic carrot (prGCD) have been previously solved. We now describe structure characteristics novel form under investigation for treatment Gene-Activated TM human...
Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation amyloid fibrils in patients' tissues. Excess are equilibrium between dimers and less stable monomers which can undergo irreversible aggregation state. The therefore must disassociate into prior forming fibrils. Here we identify ligands that inhibit stabilizing Mcg chain variable domain dimer shifting away from amyloid-prone monomer.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence resistant viral strains. In present work, novel bicyclic derived etravirine (ETV) rilpivirine (RPV), bearing modified purine, tetrahydropteridine, pyrimidodiazepine cores, were designed prepared. Compounds 2, 4, 6 carrying acrylonitrile moiety...
Abstract 6‐Amino‐6‐deoxy‐5,6‐di‐ N ‐( ′‐octyliminomethylidene)nojirimycin , a reducing analogue of ‐nonyl‐1‐deoxynojirimycin, proved to be potent and very selective inhibitor β‐glucosidases, including human acid β‐glucosidase. Structural studies the enzyme–inhibitor complex showed binding mode in which anomeric hydroxy group is accommodated “wrong” α configuration. magnified image
Gaucher disease is caused by mutations in the gene encoding acid-β-glucosidase. A recombinant form of this enzyme, Cerezyme®, used to treat patients `enzyme-replacement therapy'. Crystals Cerezyme® after its partial deglycosylation were obtained earlier and structure was solved 2.0 Å resolution [Dvir et al. (2003), EMBO Rep. 4, 704–709]. The crystal unmodified now reported, which a substantial number sugar residues bound three asparagines via N-glycosylation could be visualized. intact fully...
Cyclodextrin-based host–guest chemistry has been exploited to facilitate co-crystallization of recombinant human acid β-glucosidase (β-glucocerebrosidase, GlcCerase) with amphiphilic bicyclic nojirimycin analogues the sp2-iminosugar type. Attempts co-crystallize GlcCerase 5-N,6-O-[N′-(n-octyl)iminomethylidene]nojirimycin (NOI-NJ) or 5-N,6-S-[N′-(n-octyl)iminomethylidene]-6-thionojirimycin (6S-NOI-NJ), two potent inhibitors enzyme promising pharmacological chaperone activity for several...
Serum paraoxonases (PONs) exhibit a wide range of physiologically important hydrolytic activities, including drug metabolism and detoxification nerve gases. PON1 PON3 reside on high-density lipoprotein (HDL) (the "good cholesterol"), are involved in the alleviation atherosclerosis. Members PON family have been identified not only mammals other vertebrates, but also invertebrates. We earlier described first crystal structure member, directly-evolved variant PON1, at 2.2 A resolution. is...
The anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino-]carbonyloxycamptothecin (CPT-11) is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. It hydrolyzed by carboxylesterases to yield 7-ethyl-10-hydroxycamptothecin (SN-38), potent topoisomerase I poison. However, upon high-dose intravenous administration CPT-11, cholinergic syndrome observed can be ameliorated atropine. Previous studies have indicated CPT-11 inhibit...
Microbatch crystallization under oil is a powerful procedure for obtaining protein crystals. Using this method, aqueous solutions are dispensed liquid oil, and water evaporates through the layer of with concomitant increase in concentrations both precipitant until nucleation point reached. A technique presented regulating rate evaporation, which permits fine tuning conditions as well preventing complete desiccation drops microbatch trays.
Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment HIV-1 infection due to their high genetic barrier resistance development. Nevertheless, two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent maintain sufficient drug plasma levels which can lead undesirable drug-drug interactions. Herein, we describe GS-9770, novel investigational non-peptidomimetic PI unboosted...
Manganese is recruited in microorganisms by way of ABC-type transporter systems. Here, the expression, purification and preliminary crystallographic analysis a soluble form MntC solute-binding protein component MntABC manganese-import system from cyanobacterium Synechococystis sp. PCC 6803 reported. The (321 amino-acid residues) was expressed exclusively inclusion bodies, which required unfolding refolding presence manganese prior to purification. purified crystallized PEG zinc. crystals...