A5025395108- Chemical Synthesis and Analysis
- Prion Diseases and Protein Misfolding
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Coenzyme Q10 studies and effects
- Trace Elements in Health
- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- RNA regulation and disease
- Advanced biosensing and bioanalysis techniques
- HIV Research and Treatment
- Carbohydrate Chemistry and Synthesis
- Monoclonal and Polyclonal Antibodies Research
- Supramolecular Self-Assembly in Materials
- Neurological diseases and metabolism
- Machine Learning in Materials Science
- Infectious Encephalopathies and Encephalitis
- RNA Research and Splicing
- Antimicrobial Peptides and Activities
- Biochemical Acid Research Studies
- Crystallography and molecular interactions
- Advanced battery technologies research
Broad Institute
2019-2024
University of Wisconsin–Madison
2010-2017
Morgridge Institute for Research
2016-2017
High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand libraries can access far greater space, provided that the predictive accuracy sufficient useful Through largest and most diverse virtual HTS campaign reported date, comprising 318 individual projects, we demonstrate our AtomNet® convolutional neural network...
Prion disease is a fatal, incurable neurodegenerative of humans and other mammals caused by conversion cellular prion protein (PrPC) into self-propagating neurotoxic conformer (prions; PrPSc). Strong genetic proofs concept support lowering PrP expression as therapeutic strategy. Antisense oligonucleotides (ASOs) can provide practical route to 1 target mRNA in the brain, but their development for has been hindered 3 unresolved issues from prior work: uncertainty about mechanism action,...
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,...
We report the first high-resolution structural data for β/γ-peptide 13-helix (i,i+3 C═O···H—N H-bonds), a secondary structure that is formed by oligomers with 1:1 alternation of β- and γ-amino acid residues. Our characterization includes both crystallophaphic 2D NMR data. Previous studies suggested β/γ-peptides constructed from conformationally flexible residues adopt different helical in solution. design features preorganized γ-residues, which strongly promote 13-helical folding β/γ backbone.
The single-conformation spectroscopy of two model γ-peptides has been studied under jet-cooled conditions in the gas phase. methyl-capped triamides, Ac-γ2-hPhe-γ2-hAla-NHMe and Ac-γ2-hAla-γ2-hPhe-NHMe, were probed by resonant two-photon ionization (R2PI) ion-dip infrared (RIDIR) spectroscopies. Four conformers three Ac-γ2-hAla-γ2-hPhe-NHMe observed spectroscopically interrogated. On basis comparison with predictions density functional theory calculations employing a dispersion-corrected...
All wound up: Crystallographic data for a set of homologous peptides constructed from gabapentin and two to six preorganized γ-amino acid residues (see crystal structure the longest peptide) allow derivation characteristic parameters γ-peptide 14-helix establish guidelines characterizing 14-helical folding. The results suggest that substitution pattern γ-residue has profound effect on propensity Detailed facts importance specialist readers are published as "Supporting Information". Such...
Prion protein (PrP) concentration controls the kinetics of prion replication and is a genetically pharmacologically validated therapeutic target for disease. In order to evaluate PrP as pharmacodynamic biomarker assess its contribution known disease risk factors, we developed plate-based immunoassay reactive across 6 species interest applicable brain cerebrospinal fluid (CSF). varied dramatically different regions in mice, cynomolgus macaques, humans. expression did not appear contribute...
Abstract Diversity-oriented synthesis (DOS) is a powerful strategy to prepare molecules with underrepresented features in commercial screening collections, resulting the elucidation of novel biological mechanisms. In parallel development DOS, DNA-encoded libraries (DELs) have emerged as an effective, efficient identify protein binders. Despite recent advancements this field, most DEL syntheses are limited by presence sensitive DNA-based constructs. Here, we describe design, synthesis, and...
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
We report the asymmetric synthesis of γ-amino acid (1R,2R)-2-aminomethyl-1-cyclopentane carboxylic (AMCP) and an evaluation this residue's potential to promote secondary structure in α/γ-peptides. Simulated annealing calculations using NMR-derived distance restraints obtained for α/γ-peptides chloroform reveal that AMCP-containing oligomers are conformationally flexible. However, additional evidence suggests internally hydrogen-bonded helical conformation is partially populated solution....
Therapies currently in preclinical development for prion disease seek to lower protein (PrP) expression the brain. Trials of such therapies are likely rely on quantification PrP cerebrospinal fluid (CSF) as a pharmacodynamic biomarker and possibly trial endpoint. Studies using ELISA kits have shown that CSF is lowered symptomatic phase disease, potential confounder reading out effect PrP-lowering drugs patients. Because misfolding or proteolytic cleavage could potentially render invisible...
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...
Kristallographische Daten für einen Satz homologer Peptide, die aus Gabapentin und zwei bis sechs vororganisierten α-Aminosäureresten aufgebaut wurden (siehe Struktur des längsten Peptids), ermöglichen Ableitung charakteristischer Parameter α-Peptid-14-Helix liefern Richtlinien Charakterisierung einer 14-helicalen Faltung. Das Substitutionsmuster eines α-Rests dürfte starke Auswirkungen auf Neigung zur Faltung haben.
PrP lowering is effective against prion disease in animal models and being tested clinically. Therapies the current pipeline lower production, leaving pre-existing to be cleared according its own half-life. We hypothesized that PrP's half-life may a rate-limiting factor for time effect of PrP-lowering drugs, one reason why late treatment prion-infected mice not as early treatment. Using isotopically labeled chow with targeted mass spectrometry, well antisense oligonucleotide followed by...
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...
Summary Human COQ8A (ADCK3) and Saccharomyces cerevisiae Coq8p (collectively COQ8) are UbiB family proteins essential for mitochondrial coenzyme Q (CoQ) biosynthesis. However, the biochemical activity of COQ8 its direct role in CoQ production remain unclear, part due to lack known endogenous regulators function effective small molecules probing vivo . Here we demonstrate that possesses evolutionarily conserved ATPase is activated by binding membranes containing cardiolipin phenolic compounds...
Abstract Therapies currently in preclinical development for prion disease seek to lower protein (PrP) expression the brain. Trials of such therapies are likely rely on quantification PrP cerebrospinal fluid (CSF) as a pharmacodynamic biomarker and possibly trial endpoint. Studies using ELISA kits have reproducibly shown that CSF is lowered symptomatic phase disease, potential confounder reading out effect PrP-lowering drugs patients. To date it has been unclear whether reduced abundance...