A5063437880- Mass Spectrometry Techniques and Applications
- Analytical Chemistry and Chromatography
- Monoclonal and Polyclonal Antibodies Research
- Protein purification and stability
- Metabolomics and Mass Spectrometry Studies
- RNA Interference and Gene Delivery
- Advanced Proteomics Techniques and Applications
- Virus-based gene therapy research
- Analytical chemistry methods development
- CAR-T cell therapy research
- Chemical Synthesis and Analysis
- Microfluidic and Capillary Electrophoresis Applications
- Advanced biosensing and bioanalysis techniques
- Muscle Physiology and Disorders
- Cardiomyopathy and Myosin Studies
- Viral Infectious Diseases and Gene Expression in Insects
- Chronic Lymphocytic Leukemia Research
- Pharmacogenetics and Drug Metabolism
- bioluminescence and chemiluminescence research
- Metal-Catalyzed Oxygenation Mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- Biosimilars and Bioanalytical Methods
- Synthesis and Biological Evaluation
- Evolution and Paleontology Studies
- PI3K/AKT/mTOR signaling in cancer
Merck & Co., Inc., Rahway, NJ, USA (United States)
2016-2025
United States Military Academy
2021
Merck Institute for Science Education
2018
MSD K.K. (Japan)
2018
Amgen (United States)
2005-2017
The University of Sydney
2001-2009
California Pacific Medical Center
1995-2002
Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising a range of oxidations, practical use enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering application non-heme iron α-ketoglutarate-dependent dioxygenase direct stereo- regio-selective non-native fluoroindanone en route to oncology treatment belzutifan, replacing five-step...
The factors controlling cationic liposome-DNA complex (CLDC)-based gene transfer in cells and animals are poorly understood. We found that cell surface heparin/heparan sulfate-bearing proteoglycans mediate CLDC-based expression both cultured following intravenous delivery into animals. CLDC did not transfect Raji cells, which lack proteoglycans, but efficiently stably transfected with the proteoglycan, syndecan-1. Fucoidan, heparin, or dextran sulfate, all of highly anionic polysaccharides,...
Recent studies suggest that lysophosphatidic acid (LPA) and its G protein-coupled receptors (GPCRs) LPA 1 , 2 or 3 may play a role in the development of several types cancers, including colorectal cancer. However, specific receptor subtype(s) their signal-transduction pathways responsible for LPA-induced cancer cell proliferation have not been fully elucidated. We show by RNA interference (RNAi) but are targets HCT116 LS174T colon cells. determined requires β-catenin signaling pathway,...
Two radical-based approaches have been developed to effect the trifluoromethylation of aryl C-H bonds in native peptides either using stoichiometric oxidant or visible light photoredox catalysis. The reported methods are able derivatize tyrosine and tryptophan sidechains under biocompatible conditions, a number examples involving fully unprotected with up 51 amino acids. development this chemistry adds growing array chemical for selectively modifying acid residues context complex peptides....
The emergence of new therapeutic modalities requires complementary tools for their efficient syntheses. Availability methodologies site-selective modification biomolecules remains a long-standing challenge, given the inherent complexity and presence repeating residues that bear functional groups with similar reactivity profiles. We describe bioconjugation strategy native peptides relying on high site selectivity conveyed by enzymes. engineered penicillin G acylases to distinguish among free...
Drug-induced nephrotoxicity is a major challenge in drug discovery and development, accounting for nearly quarter of severe adverse effects current pharmacotherapy. Antimicrobial use may be associated with this problem, one-third related to these drugs. During the lead optimization stage our antibacterial programs, was observed renal tubule degeneration tubular granular casts. To examine mechanisms triage compounds, matrix-assisted laser desorption/ionization mass spectrometry imaging...
Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues ProTx-II that safely display systemic vivo blocking Nav1.7, resulting a latency response thermal stimuli rodents. new designs achieve better profile by improving selectivity and limiting ability peptides cause mast cell degranulation. rationale, structural modeling, vitro...
Limb muscles of eutherian (placental) mammals express a slow and three fast isoforms myosin heavy chain (MyHC), but little is known about marsupial MyHCs. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) limb MyHCs from seven species, spanning two orders, revealed four components, each which specifically cross-reacted in Western blots with monoclonal antibody (mAb) against corresponding MyHC. For all the relative mobility band identified by mAb matched that rat,...
An integrated online-offline platform was developed combining automated online LC-MS fraction collection, continuous accumulation of selected ions (CASI), and offline top-down electron capture dissociation (ECD) tandem mass spectrometry experiments to identify a low-level, unknown isomeric degradant in formulated drug product during an accelerated stability study. By identifying the diagnostic isoaspartic acid (isoAsp), ECD experiment showed that Asp9 exenatide converted isoAsp9 form...
The ability to measure low levels of (2)H-labeling is important in studies metabolic flux, e.g. one can estimate lipid synthesis by administering (2)H2O and then measuring the incorporation (2)H into fatty acids. Unfortunately, analyses are complicated presence more abundant naturally occurring stable isotopes, (13)C. Conventional approaches rely on coupling gas chromatographic separation lipids with either quadrupole-mass spectrometry (q-MS) and/or pyrolysis-isotope ratio mass (IRMS)....
Transition metals can be introduced in therapeutic protein drugs at various steps of the manufacturing process (e.g. raw materials, formulation, storage), and cause a variety modifications on protein. These potentially influence efficacy, safety, stability protein, especially if critical quality attributes (CQAs) are affected. Therefore, it is meaningful to understand interactions between proteins that occur during process, storage biotherapeutics. Here, we describe novel strategy...
The process development for 2′F-thio-adenosine monophosphate, an intermediate MK-1454, immunooncology therapeutic, is described. Kinetic profiling, nuclear magnetic resonance monitoring, investigation of product decomposition pathways, and crystallization control identified important parameters efficient thiophosphorylation process. Among those are the use pivaloyl as protecting group nucleoside starting material well triethylphosphate a green reaction solvent, both which critical allowing...
Cyclodextrin (CD) perfunctionalization reactions are challenging to study because they proceed through a number of regioisomeric intermediates, thus warranting creative approaches understanding the reaction mechanism. Particularly useful targets per(6-deoxy-6-halo)cyclodextrins. Their standard synthesis entails selective SN2 halogenation at their primary alcohols using Vilsmeier reagent, but this requires strongly basic quench unmask Vilsmeier-capped secondary alcohols. Herein we present an...