Becton Dickinson and Company Limited

University of Michigan

Leland Stanford Junior University

University of California

University of South Florida

Jason E Gestwicki

J Bruce Pitner

Helen V Hsieh

Zachary A Pfieffer

Gerald R Crabtree

Isabella A Graef

James R Baker, Jr

Chad Dickey

Theodore B Norris

Tommaso F Bersano-Begey

Kathryn McMenimen

Leah Makley

Jingyong Ye

Xiaokai Li

Brian DeVree

Provided herein are compounds of formula (I) which are, inter alia, useful allosteric inhibitors of Hsp70. The compounds and methods provided are useful for the treatment of cancer, infectious and neurodegenerative diseases.

Oxathiazole thiazolium Hsp 70 inhibitors

Disclosed are compounds of formula (l)-(V): where the substituents are as provided herein. Further disclosed are methods of inhibiting tau aggregation, treating or ameliorating a tauopathy or cancer by administration of such a compound. Tau is a microtubule-binding protein that accumulates in a number of neurodegenerative disorders, including frontotemporal dementia and Alzheimer's disease (AD). The presence of abnormal tau correlates with neuron loss and memory deficits in patients with AD and other neurodegenerative disorders that involve tau accumulation.

Pharmaceutical compounds and use of same in cancer and tauopathies

The invention provides inhibitors of &#x3b1;-crystallin aggregation and methods of using &#x3b1;-crystallin aggregation inhibitors to, e.g., treat or prevent cataracts in a subject having or at risk of developing cataracts. The invention further provides high throughput methods of screening compounds for modulation of protein thermal stability, the method comprising contacting a protein with each of a plurality of test compounds; and (b) measuring the melting transition (T) of the protein in the presence of each of the plurality of test compounds, wherein a compound that decreases or increases the apparent Tby at least 2 standard deviations is identified as a pharmacological protein chaperone.

Non-surgical method of treatment for cataract

Disclosed are compounds of formula (1)-(V): where the substituents are as provided herein. Further disclosed are methods of inhibiting tau aggregation, treating or ameliorating a tauopathy or cancer by administration of such a compound. Tau is a microtubule-binding protein that accumulates in a number of neurodegenerative disorders, including frontotemporal dementia and Alzheimer's disease (AD). The presence of abnormal tau correlates with neuron loss and memory deficits in patients with AD and other neurodegenerative disorders that involve tau accumulation.

A system for determining whether interaction occurs between a trial substance and a target substance. The system includes a photonic crystal sensor having a photonic crystal structure and a defect member disposed adjacent the photonic crystal structure. The defect member defines an operative surface able to receive the target substance and the trial substance. The system further includes a light source that inputs a light signal to the photonic crystal structure and the defect member. The light signal is internally reflected, and a resultant output signal is outputted. The output signal relates to whether the trial substance interacts with the target substance at the operative surface. Furthermore, the system includes an identity detector that identifies the trial substance that interacts with the target substance.

Analytical system with photonic crystal sensor

Methods and compositions are provided for reducing aggregation of neurodegenerative proteins associated with neurotoxicity or other proteins. The compounds comprise a first domain or targeting element for binding to the target proteins linked to a second domain or recruiting element that binds to an aggregation inhibiting protein, e.g. a prolyl isomerase. By associating the aggregating forming proteins or neuronal cells under conditions where aggregating proteins are produced with the compound and the aggregation inhibiting protein, aggregation is reduced. The subject agents can be used in assays, investigating the etiology of the neuronal diseases and for prophylaxis and therapy.

Neurodegenerative protein aggregation inhibition methods and compounds

The invention is directed to compositions of mutated binding proteins containing thiol groups for coupling to sensor surfaces, analyte biosensor devices derived there from, and methods of their use as analyte biosensors both in vitro and in vivo.

Binding proteins as biosensors

Binding protein as biosensors

Methods for detection and analysis of allosteric receptor/ligand binding by changes in surface refractive index are provided. When analyzed by surface plasmon resonance, binding of such allosteric binding agents to their ligands may result in a negative deviation in the optical response (i.e., a decrease in resonance angle) or in an increase in the optical response (i.e., an increase in resonance angle) depending on the binding properties of the selected allosteric receptor. Other methods for analysis of surface refractive index are also useful in the invention. The methods of the invention are particularly useful for small ligands which would not be expected to produce detectable changes in refractive index because they do not add significant mass upon binding.

Growing community of inventors

Mountain View, CA, United States of America

Jason E Gestwicki