A5072256823- Prion Diseases and Protein Misfolding
- Monoclonal and Polyclonal Antibodies Research
- Lipid metabolism and disorders
- Atherosclerosis and Cardiovascular Diseases
- HIV Research and Treatment
- Genetic Associations and Epidemiology
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Protease and Inhibitor Mechanisms
- Advanced NMR Techniques and Applications
- RNA regulation and disease
- Bacteriophages and microbial interactions
- Angiogenesis and VEGF in Cancer
- Cerebrovascular and genetic disorders
- Chemical Synthesis and Analysis
- Cancer therapeutics and mechanisms
- vaccines and immunoinformatics approaches
- Hemoglobin structure and function
- Trace Elements in Health
- Liver Disease Diagnosis and Treatment
- Health and Medical Research Impacts
- Cardiac, Anesthesia and Surgical Outcomes
- Venomous Animal Envenomation and Studies
- RNA Research and Splicing
- Glycosylation and Glycoproteins Research
Broad Institute
2014-2024
Harvard University
2009
Georgetown University Medical Center
2002
Georgetown Lombardi Comprehensive Cancer Center
2002
Georgetown University
2002
Antisense oligonucleotides (ASOs) designed to lower prion protein (PrP) expression in the brain through RNase H1-mediated degradation of PrP RNA are development as disease therapeutics. ASOs were previously reported sequence-independently interact with and inhibit accumulation cell culture, yet vivo studies using a new generation found that only PrP-lowering sequences effective at extending survival. Cerebrospinal fluid (CSF) has been proposed pharmacodynamic biomarker for trials such ASOs,...
Paramagnetic metal centers [such as FeIII found within ferriprotoporphyrin IX heme (FPIX)] exert through space effects on the relaxation rate of nearby proton spins that depend critically metal−proton distance. We have measured these for all protons several antimalarial drugs bind to FPIX by systematically varying drug:heme molar ratio in high field NMR experiments. These measurements allow us determine precise Fe−drug H distances solution structures noncovalent complexes formed between...
Crystallization of a maltose-binding protein MCL1 fusion has yielded robust crystallography platform that generated the first apo crystal structure, as well five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In ligand-independent form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1...
Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), there are currently no therapeutic options. PrP ligands could theoretically antagonize formation protecting native from or targeting it for degradation, but validated small-molecule binders have been discovered to date. We deployed variety screening methods in an effort discover PrP, including
DNA-Encoded Library (DEL) technology allows the screening of millions, or even billions, encoded compounds in a pooled fashion which is faster and cheaper than traditional approaches. These massive amounts data related to DEL binders not-binders target interest enable Machine Learning (ML) model development large, readily accessible, drug-like libraries an ultra-high-throughput fashion. Here, we report comparative assessment DEL+ML pipeline for hit discovery using three DELs five ML models...
A direct binding screen of 100 000 sp3-rich molecules identified a single diastereomer macrolactam core that binds specifically to myeloid cell leukemia 1 (MCL1). comprehensive toolbox biophysical methods was applied validate the original hit and subsequent analogues also established mode competitive with NOXA BH3 peptide. X-ray crystallography ligand bound MCL1 reveals remarkable ligand/protein shape complementarity diverges from previously disclosed inhibitor costructures.
Abstract Aims Genetic studies have implicated the ARHGEF26 locus in risk of coronary artery disease (CAD). However, causal pathways by which DNA variants at confer for CAD are incompletely understood. We sought to elucidate mechanism responsible enhanced associated with locus. Methods and results In a conditional analysis locus, we show that sentinel CAD-risk signal is significantly various non-lipid vascular phenotypes. human endothelial cell (EC), promotes angiogenic capacity, interacts...
Abstract Antisense oligonucleotides (ASOs) designed to lower prion protein (PrP) expression in the brain through RNAse H1-mediated degradation of PrP RNA are development as disease therapeutics. ASOs were previously reported sequence-independently interact with and inhibit accumulation cell culture, yet vivo studies using a new generation found that only PrP-lowering sequences effective at extending survival. Cerebrospinal fluid (CSF) has been proposed pharmacodynamic biomarker for trials...
ABSTRACT Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), there are currently no therapeutic options. PrP ligands could theoretically antagonize formation protecting native from or targeting it for degradation, but validated small-molecule binders have been discovered to date. We deployed variety screening methods in an effort discover PrP, including 19 F-observed saturation transfer difference (STD) nuclear...
Vascular inflammation drives the initiation and progression of coronary artery disease (CAD). However, underlying genetic factors are not well understood. We performed a genome-wide association study in UK Biobank testing 9 million DNA variants for with CAD (4,831 cases, 115,455 controls), followed by meta-analysis previous results. identified ARHGEF26 (Rho guanine nucleotide exchange factor 26) as novel locus significantly associated (combined OR=1.08, 95% CI 1.06-1.11, P=1.02 х 10 –9 )....