A5067161412- Alzheimer's disease research and treatments
- Prion Diseases and Protein Misfolding
- Connexins and lens biology
- Neurological diseases and metabolism
- Heat shock proteins research
- 14-3-3 protein interactions
- Protein Structure and Dynamics
- Enzyme Structure and Function
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Trace Elements in Health
- Cholinesterase and Neurodegenerative Diseases
- RNA Research and Splicing
- Nuclear Receptors and Signaling
- Glycosylation and Glycoproteins Research
- Bioinformatics and Genomic Networks
- COVID-19 Clinical Research Studies
- Neurological disorders and treatments
- Parkinson's Disease Mechanisms and Treatments
- Insect and Pesticide Research
- Click Chemistry and Applications
- Calpain Protease Function and Regulation
- Amyotrophic Lateral Sclerosis Research
- Amyloidosis: Diagnosis, Treatment, Outcomes
- SARS-CoV-2 and COVID-19 Research
NeuroHealing Pharmaceuticals (United States)
2011-2016
Whitehead Institute for Biomedical Research
2004-2012
University of Chicago
2004
New York University
2004
University of Illinois Chicago
2004
Howard Hughes Medical Institute
2004
Centre for Cellular and Molecular Biology
1996-2001
Montserrat Volcano Observatory
1996
The yeast prion protein Sup35 is a translation termination factor, whose activity modulated by sequestration into self-perpetuating amyloid. prion-determining domain, NM, consists of two distinct regions: an amyloidogenic N terminus domain (N) and charged solubilizing middle region (M). To gain insight conversion, we used single-molecule fluorescence resonance energy transfer (SM-FRET) correlation spectroscopy to investigate the structure dynamics monomeric NM. Low concentrations in these...
Prions are infectious protein conformations that generally ordered aggregates. In the absence of prions, newly synthesized molecules these same proteins usually maintain a conventional soluble conformation. However, prions occasionally arise even without homologous prion template. The conformational switch results in de novo appearance yeast with glutamine/aspargine (Q/N)-rich domains (e.g., [ PSI + ]), is promoted by heterologous similar domain RNQ ], also known as PIN or overexpression...
Some amyloid-forming polypeptides are associated with devastating human diseases and others provide important biological functions. For both, oligomeric intermediates appear during amyloid assembly. Currently we have few tools for characterizing these conformationally labile discerning what governs their benign versus toxic states. Here, examine in the assembly of a normal, functional amyloid, prion-determining region yeast Sup35 (NM). During assembly, NM formed variety oligomers different...
α-Crystallin, a multimeric protein, exhibits chaperone-like activity in preventing aggregation of several proteins. We have studied the α-crystallin toward heat-induced bovine and human carbonic anhydrase. Human anhydrase aggregates at 60°C, while does not aggregate significantly this temperature. Removal enzyme-bound metal ion, Zn2+, by EDTA modulates behavior Fluorescence circular dichroism studies show that removal ion from chelator such as enhances propensity enzyme to adopt...
Alzheimer's disease (AD) is characterized by appearance of both extracellular senile plaques and intracellular neurofibrillary tangles, comprised aggregates misfolded amyloid-β (Aβ) hyper-phosphorylated tau, respectively. In a previous study, we demonstrated that g3p, capsid protein from bacteriophage M13, binds to remodels proteins assume an amyloid conformation. We engineered fusion ("NPT088") consisting the active fragment g3p human-IgG1-Fc.Aged Tg2576 mice or rTg4510 received NPT088...
We have investigated the role of recombinant human alphaA- and alphaB-crystallins in heat-induced inactivation aggregation citrate synthase. Homo-multimers both confer protection against a concentration-dependent manner also prevent aggregation. Interaction crystallins with early unfolding intermediates synthase reduces their partitioning into aggregation-prone intermediates. This appears to result enhanced population that can be reactivated by its substrate, oxaloacetate. Both these...
Mechanisms to safely eliminate amyloids and preamyloid oligomers associated with many devastating diseases are urgently needed. Biophysical principles dictate that small molecules unlikely perturb large intermolecular protein–protein interfaces, let alone extraordinarily stable amyloid interfaces. Yet 4,5-dianilinophthalimide (DAPH-1) reverses Aβ42 amyloidogenesis neurotoxicity, which is Alzheimer's disease. Here, we show DAPH-1 select derivatives ineffective against several amyloidogenic...
The accumulation of combinations aggregated amyloid-β, tau, and α-synuclein within a single disease, such as found in Alzheimer's disease (AD), evokes therapeutic strategies that generically target aggregates, independent primary protein sequence. NPT088 is human immunoglobulin (huIgG1Fc) fusion displays two copies the General Amyloid Interaction Motif (GAIM). We have shown has uniquely broad activities, both vitro vivo, against multiple neuropathological making it novel candidate for...
Abstract Parkinson’s disease and multiple system atrophy are members of a class devastating neurodegenerative diseases called synucleinopathies, which characterized by the presence alpha-synuclein (α-Syn) rich aggregates in brains patients. Passive immunotherapy targeting these is an attractive disease-modifying strategy. Such approach must not only demonstrate target selectivity towards α-Syn aggregates, but also achieve appropriate brain exposure to have desired therapeutic effect. Here we...
We have previously described the discovery and development of GAIM (general amyloid interaction motif)-Ig (immunoglobulin) fusions as therapeutic candidates for neurodegenerative indications [1,2]....
<h3>Background</h3> COVID-19 is a global public health crisis with no effective therapeutic strategies or vaccines available. The disease caused by the SARS-CoV-2 virus, novel coronavirus that enters cells through ACE2 receptor. To rapidly identify existing drugs might preferentially bind to receptor we sought use an artificial intelligence platform evaluate ~3,000 known in FDA approved drug library (Selleckchem). <h3>Methods</h3> Fluency quantitative structure–activity relationship (QSAR)...
Alzheimer's disease (AD) is characterized by both Amyloid b (A b) plaque deposition and intracellular neurofibrillary tangles accompanied progressive cognitive decline. We isolated a protein motif from M13 bacteriophage that binds to disaggregates multiple amyloids, which we call the General Interaction Motif or GAIM. The present studies were conducted evaluate whether NPT088, Hu-IgG 1 -Fc fusion bivalent for GAIM was able mediate clearance of A plaques reduction phospho-Tau (pTau) in...
Protein misfolding that produces assemblies of toxic and transmissible aggregates is a central feature the pathobiology neurodegenerative diseases. A serendipitous discovery direct exposure to filamentous bacteriophage M13 mediates reductions both Aβ tau deposits in brains transgenic mouse models Alzheimer's disease led search for mechanism. We have isolated characterized fragment phage capsid protein responsible amyloid targeting activities M13, we show an immunoglobulin fusion this motif...
Alzheimer's disease (AD) is characterized by both Amyloid b (Aβ) plaque deposition and intracellular neurofibrillary tangles accompanied progressive cognitive decline. We have shown that NPT002 (filamentous bacteriophage M13) dose-dependently clears Aβ plaques restores normal performance in aged Tg2576 mice. Recently, we isolated the protein motif from responsible for amyloid-interacting activity, which call generic amyloid interacting or GAIM. The present study was conducted to evaluate...
Misfolded protein aggregates play a central role in the pathobiology of neurodegenerative diseases. Using biophysical and biochemical methods, we established that purified, formulated filamentous bacteriophage M13 (NPT002) directly potently(binding KD=4–7 nM) destabilizes dissociates broad class amyloids, including amyloid-β, tau, yeast prion, mammalian andalpha-synuclein. We have shown NPT002 mediates lowering misfolded following single intracranial administrations to transgenic mouse...
Diagnostic hallmarks of AD include both extracellular ß-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs), accumulating over decades before symptomatic disease onset. The significance amyloids for neuronal toxicity cognitive deterioration has been established in animal models implicated human progression. Intensive drug discovery efforts have directed toward lowering types deposits. Plaques are composed fibrils aggregated amyloid-ß (fAß), NFTs microtubule-binding protein tau....