A5103030947- Parkinson's Disease Mechanisms and Treatments
- Enzyme Production and Characterization
- CRISPR and Genetic Engineering
- Cholinesterase and Neurodegenerative Diseases
- Epigenetics and DNA Methylation
- Protein Structure and Dynamics
- Plant Gene Expression Analysis
- Biotechnology and Related Fields
- Biochemical and Structural Characterization
- Enzyme Catalysis and Immobilization
- Plant biochemistry and biosynthesis
- Computational Drug Discovery Methods
- Bacterial Genetics and Biotechnology
- X-ray Diffraction in Crystallography
- Cancer-related gene regulation
- Carbohydrate Chemistry and Synthesis
- HIV Research and Treatment
- Crystallization and Solubility Studies
- Enzyme Structure and Function
- Protein purification and stability
- Synthetic Organic Chemistry Methods
Merck & Co., Inc., Rahway, NJ, USA (United States)
2021-2024
Johns Hopkins University
2015-2019
New York University
2010-2015
SUNY Polytechnic Institute
2010
Metropolitan Community College
2010
Abstract Mammalian genomes exhibit complex patterns of gene expression regulated, in part, by DNA methylation. The advent engineered methyltransferases (MTases) to target methylation specific sites the genome will accelerate many areas biological research. However, targeted MTases require clear design rules direct site-specific and minimize unintended effects off-target Here we report a MTase composed an artificially split CpG (sMTase) with one fragment fused catalytically-inactive Cas9...
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling progressive neurodegenerative disorder whose current therapies are limited in scope efficacy. In this report, we describe rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated the discovery of brain-penetrant, candidate-quality molecules as represented compounds 22 24. These exhibit remarkable selectivity against...
Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment Parkinson's disease. We previously disclosed discovery an indazole series lead that demonstrated both safety and translational risks. The risks were hypothesized to be unknown origin, so structural diversity in subsequent chemical matter was prioritized. identified due low brain Kp
Inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization novel series potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type ATP-competitive physicochemical properties were integrated with CNS drug-like through combination structure-based drug...
Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid efficacious disease-modifying therapies. Herein, we describe invention an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, property-based drug design in concert rigorous application silico calculations presynthesis predictions enabled prioritization molecules...
Insertional fusion between host and guest protein domains has been employed to create multi-domain complexes displaying integrated coupled functionalities. The effects of insertional on the stability a are however rather controversial. In study described here, we examined whether inserted TEM1 beta-lactamase (BLA), as protein, might be affected by maltodextrin-binding (MBP), protein. Our results indicate that expression levels in vitro BLA domain were significantly higher when into...
Abstract A universal method that improves protein stability and evolution has thus far eluded discovery. Recently, however, studies have shown insertional fusion to a chaperone stabilized various target proteins with minimal negative effects. The improved was derived from insertion into hyperthermophilic protein, Pyrococcus furiosus maltodextrin‐binding (PfMBP), rather than changes the sequence. In this report, by evaluating thermodynamic kinetic of inserted β‐lactamase (BLA) homologues, we...
Mammalian gene expression is a complex process regulated in part by CpG methylation. The ability to target methylation for de novo regulation could have therapeutic and research applications. We previously developed dCas9-MC/MN protein targeting composed of an artificially split M.SssI methyltransferase (MC/MN), with the MC fragment fused nuclease-null CRISPR/Cas9 (dCas9). Guide RNAs directed methylate sites E. coli human cells but also caused some low-level off-target Here, coli, we show...
The protein design rules for engineering allosteric regulation are not well understood. A fundamental understanding of the determinants ligand binding in an context could facilitate and construction versatile switches biosensors. Here, we conducted extensive vitro vivo characterization effects 285 unique point mutations at 15 residues maltose-binding pocket maltose-activated β-lactamase MBP317-347. MBP317-347 is enzyme formed by insertion TEM-1 into E. coli maltose (MBP). We find that...
ABSTRACT We present polysaccharide-based nanoparticles able to associate and increase the catalytic activity of maltose-binding MBP317-347 switch enzyme. Fluorescence quenching molecular docking studies along with partial resistance increasing pH ionic strength indicate that in enzymatic is due a specific interaction between maltose binding pocket on alginate exposed surface nanoparticles. Finally, we show hybrid self co-assembled particles half-life over six-fold at 37°C, thus reflecting...