A5009899105- Synthetic Organic Chemistry Methods
- Endoplasmic Reticulum Stress and Disease
- Ubiquitin and proteasome pathways
- CRISPR and Genetic Engineering
- Asymmetric Synthesis and Catalysis
- Advanced Drug Delivery Systems
- Lanthanide and Transition Metal Complexes
- Cancer-related Molecular Pathways
- Electron and X-Ray Spectroscopy Techniques
- RNA regulation and disease
- Monoclonal and Polyclonal Antibodies Research
- Chemical Synthesis and Analysis
- Nanoparticle-Based Drug Delivery
- Oxidative Organic Chemistry Reactions
- Induction Heating and Inverter Technology
- Microtubule and mitosis dynamics
- Magnetic Properties and Applications
- Cell death mechanisms and regulation
- Silicon Carbide Semiconductor Technologies
- Microbial Natural Products and Biosynthesis
- Electron Spin Resonance Studies
- Fuel Cells and Related Materials
- Antimicrobial Peptides and Activities
- Mass Spectrometry Techniques and Applications
- Metal complexes synthesis and properties
Mission Bio (United States)
2023
ProLynx (United States)
2015-2021
University of California, San Francisco
2012-2020
SUNY Upstate Medical University
2006
University of Notre Dame
1998-2005
Johns Hopkins University
2003
Stanford University
2003
University of Sheffield
2003
University of Strathclyde
2003
University of Chicago
2003
Phosphorylation of the α-subunit initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating unique serine in eIF2α. This collection signaling pathways is termed 'integrated response' (ISR). phosphorylation diminishes synthesis, while allowing preferential translation some mRNAs. Starting with cell-based screen for inhibitors PERK signaling,...
The general translation initiation factor eIF2 is a major translational control point. Multiple signaling pathways in the integrated stress response phosphorylate serine-51, inhibiting nucleotide exchange by eIF2B. ISRIB, potent drug-like small molecule, renders cells insensitive to eIF2α phosphorylation and enhances cognitive function rodents blocking long-term depression. ISRIB was identified phenotypic cell-based screen, its mechanism of action remained unknown. We now report that an...
The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of promotes cell survival cancer models. We used cell-based screens discover and develop Ceapins, class pyrazole amides, that block signaling Ceapins sensitize stress without impacting viability unstressed cells. are highly specific inhibitors signaling, not affecting through other branches UPR, or proteolytic processing its...
We evaluate experimentally and computationally the membrane permeability of matched sets peptidic small molecules bearing natural or bioisosteric unnatural amino acids. find that intentional introduction hydrogen bond acceptor–donor pairs in such can improve while retaining improving other favorable drug-like properties. employ an all-atom force field based method to calculate changes free energy associated with transfer from water membrane. This computational correctly predicts rank order...
We have developed an approach to prepare drug-releasing Tetra-PEG hydrogels with exactly four cross-links per monomer. The gels contain two cleavable β-eliminative linkers: one for drug attachment that releases the at a predictable rate, and longer half-life placed in each cross-link control biodegradation. Thus, system can be optimized release before significant gel degradation occurs. synthetic involves placing heterobifunctional connector end of four-arm PEG prepolymer; unique end-groups...
Abstract The goal was to develop and characterize a companion diagnostic for the releasable PEG40kDa∼SN-38 oncology drug, PLX038, that would identify tumors susceptible high accumulation of PLX038. PEG conjugates zirconium ligand desferroxamine B (DFB) similar size charge PLX038 were prepared contained one or four DFB, as well three SN-38 moieties DFB. Uptake associated kinetic parameters 89Zr-labeled nanocarriers determined in tumor normal tissues mice using μPET/CT imaging. data fit...
To eliminate apicomplexan parasites, inhibitory compounds must cross host cell, parasitophorous vacuole, and parasite membranes cyst walls, making delivery challenging. Here, we show that short oligomers of arginine enter Toxoplasma gondii tachyzoites encysted bradyzoites. Triclosan, which inhibits enoyl-ACP reductase (ENR), conjugated to enters extracellular tachyzoites, cells, inside vacuoles within bradyzoites, bradyzoites cysts. We identify, clone, sequence T. enr produce characterize...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSolubility of cupric oxide in pure subcritical and supercritical waterBrian Hearn, Michael R. Hunt, Alan HaywardCite this: J. Chem. Eng. Data 1969, 14, 4, 442–447Publication Date (Print):October 1, 1969Publication History Published online1 May 2002Published inissue 1 October 1969https://pubs.acs.org/doi/10.1021/je60043a031https://doi.org/10.1021/je60043a031research-articleACS PublicationsRequest reuse permissionsArticle...
Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization potent inhibitor that acts by an uncompetitive binding mode unprecedented mechanism inhibition this target class. Biochemical assays demonstrate that, while exquisitely over caspase-3 -7, compound's inhibitory activity also dependent on amino acid sequence P1' character peptide...
Ubiquitin specific protease 7 (USP7) regulates the protein stability of key cellular regulators in pathways ranging from apoptosis to neuronal development, making it a promising therapeutic target. Here we used an engineered, activated variant USP7 catalytic domain perform structure–activity studies electrophilic peptidomimetic inhibitors. Employing this variant, found that inhibitors with cyanopyrrolidine warhead unexpectedly promoted β-elimination reaction initial covalent adducts, thereby...
A linear but concise synthetic approach toward the structurally related natural products myriaporone and tedanolide is reported. The route highlighted by a stereoselective homoallenylboration regio- chemoselective nitrile oxide cycloaddition. Installation of (Z)-olefin completed carbon skeleton 1.
Abstract Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting active site. Allosteric modulation caspase activity is an alternate strategy that potentially avoids need for anionic and electrophilic functionality present in most active‐site inhibitors. Caspase‐6 has been implicated neurodegenerative disease, including Huntington’s Alzheimer’s diseases. Herein we describe a fragment‐based lead discovery effort...
We have developed a chemically controlled very long-acting delivery system to support once-monthly administration of peptidic GLP-1R agonist. Initially, the prototypical agonist exenatide was covalently attached hydrogel microspheres by self-cleaving β-eliminative linker; after subcutaneous injection in rats, peptide slowly released into systemic circulation. However, short serum half-life suggested its degradation depot. found that undergoes deamidation at Asn28 with an vitro and vivo...
The tedanolide and myriaporone classes of natural products represent interesting targets for synthesis because their structural similarity biological activity. asymmetric preparation a potential common intermediate in the total each these is presented. key step, Zr-mediated allylation, allows efficient hydroxypropionate unit.
Herpesviruses rely on a homodimeric protease for viral capsid maturation. A small molecule, DD2, previously shown to disrupt dimerization of Kaposi's sarcoma-associated herpesvirus (KSHV Pr) by trapping an inactive monomeric conformation and two analogues generated through carboxylate bioisosteric replacement (compounds 2 3) were inhibit the associated proteases all three human (HHV) subfamilies (α, β, γ). Inhibition data reveal that compound has potency comparable or better than DD2 against...
Abstract The integrated stress response comprises multiple signaling pathways for detecting and responding to cellular that converge at a single event—the phosphorylation of Ser51 on the α‐subunit eukaryotic translation initiation factor 2 (eIF2α). Phosphorylation eIF2α (eIF2α‐P) results in attenuation global protein synthesis via inhibitory effects eIF2α‐P eIF2B, guanine exchange (GEF) eIF2. Herein we describe structure–activity relationship (SAR) studies bis‐ O ‐arylglycolamides,...
The utility of antigen-binding antibody fragments is often limited by their short half-lives. Half-life extension such usually accomplished attachment or binding to high-molecular-weight carriers that reduce the renal elimination rate. However, higher hydrodynamic radius results in greater confinement vascular compartment and, thus, lower tissue distribution. We have developed a chemically controlled drug delivery system which covalently attached hydrogel microspheres self-cleaving...
Evaluation of the hypothemycin cytotoxicity SAR identifies C4′–C8′ region macrocyclic lactone as relatively intolerant structural modifications. Manipulation 4-position resorcylic acid, however, provides new opportunities to improve solubility and pharmacokinetic properties this site may be modified without negatively impacting cytotoxicity. Supporting information for article is available on WWW under http://www.wiley-vch.de/contents/jc_2452/2007/z700128_s.pdf or from author. Please note:...
β-Elimination of drugs tethered to macromolecular carbamates provides a platform for drug half-life extension. However, the Michael acceptor products formed upon release can potentially react with biological amines and thiols may raise concerns about safety. We desired mitigate this possibility by developing linkers that have predictable rates β-elimination but suppressed nucleophilic addition their products. prepared β-eliminative contained methyl group at Cβ carbon or gem-dimethyl Cγ...