# US 9,518,284 B2 · Yeast screens for treatment of human disease

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- Number: US 9,518,284 B2
- Document ID: US9518284B2
- Status: Granted
- Kind: B2
- Application number: 14/105,500
- Filed: 2013-12-13
- Published: 2014-09-18
- Granted: 2016-12-13
- Earliest claimed: 2001-02-15
- Assignees: The University of Chicago
- Applicants: The University of Chicago
- Inventors: Susan Lindquist; Sylvia Krobitsch; Tiago Fleming Outeiro
- Web page: https://patentgrep.com/patent/US9518284B2

## CPC

- C12Q 1/18: Testing for antimicrobial activity of a material
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C12Q 1/02: involving viable microorganisms
- C12Q 1/025: {for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics (antimicrobial activity C12Q1/18)}
- G01N 33/6896: {Neurological disorders, e.g. Alzheimer's disease}
- G01N 2333/4703: Regulators; Modulating activity
- G01N 2500/00: Screening for compounds of potential therapeutic value
- G01N 2800/2835: Movement disorders, e.g. Parkinson, Huntington, Tourette
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Screening methods for identifying substances that provide therapeutic value for various diseases associated with protein misfolding are provided. Genetic and chemical screening methods are provided using a yeast system. The methods of the invention provide a rapid and cost-effective method to screen for compounds that prevent protein misfolding and/or protein fibril formation and/or protein aggregation which includes numerous neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Huntington's disease as well as non-neuronal diseases such as type 2 diabetes.

## Claims

### Claim 1

A method of screening for a compound that decreases toxicity associated with ataxin-1, ataxin-2, ataxin-3, ataxin-7, calcium channel, androgen receptor, atrophin-1, SOD1, immunoglobulin light chain, transthyretin, tau, serum amyloid A, islet amyloid polypeptide, insulin, beta2-microglobulin, cystatin-C, gelsolin, or lysozyme, the method comprising:
providing a yeast cell engineered to express a protein comprising a ataxin-1, ataxin-2, ataxin-3, ataxin-7, calcium channel, androgen receptor, atrophin-1, SOD1, immunoglobulin light chain, transthyretin, tau, serum amyloid A, islet amyloid polypeptide, insulin, beta2-microglobulin, cystatin-C, gelsolin, or lysozyme polypeptide;
contacting the yeast cell with a candidate compound; and
evaluating the yeast cell for viability, wherein an increase in viability of the yeast cell as compared to viability of the yeast cell in the absence of the candidate compound indicates that the candidate compound decreases toxicity associated with ataxin-1, ataxin-2, ataxin-3, ataxin-7, calcium channel, androgen receptor, atrophin-1, SOD1, immunoglobulin light chain, transthyretin, tau, serum amyloid A, islet amyloid polypeptide, insulin, beta2-microglobulin, cystatin-C, gelsolin, or lysozyme.

### Claim 2 (depends on 1)

The method of claim 1, wherein the candidate compound is a small organic compound having a molecular weight of more than 50 daltons and less than 750 daltons or a nucleic acid.

### Claim 3

A method of screening for a compound that decreases toxicity associated with ataxin-1, ataxin-2, ataxin-3, ataxin-7, calcium channel, androgen receptor, atrophin-1, SOD1, immunoglobulin light chain, transthyretin, tau, serum amyloid A, islet amyloid polypeptide, insulin, beta2-microglobulin, cystatin-C, gelsolin, or lysozyme, the method comprising:
contacting a yeast cell with a candidate compound, wherein the yeast cell expresses a protein comprising a ataxin-1, ataxin-2, ataxin-3, ataxin-7, calcium channel, androgen receptor, atrophin-1, SOD1, immunoglobulin light chain, transthyretin, tau, serum amyloid A, islet amyloid polypeptide, insulin, beta2-microglobulin, cystatin-C, gelsolin, or lysozyme polypeptide;
contacting the yeast cell with a toxicity inducing agent; and
evaluating the yeast cell for viability, wherein an increase in viability of the yeast cell as compared to viability of the yeast cell in the absence of the candidate compound indicates that the candidate compound decreases toxicity associated with ataxin-1, ataxin-2, ataxin-3, ataxin-7, calcium channel, androgen receptor, atrophin-1, SOD1, immunoglobulin light chain, transthyretin, tau, serum amyloid A, islet amyloid polypeptide, insulin, beta2-microglobulin, cystatin-C, gelsolin, or lysozyme.

### Claim 4 (depends on 3)

The method of claim 3, wherein the toxicity inducing agent is a carbon source, nitrogen source, chemotherapeutic agent, alcohol, translation inhibitor, NSAID, DNA intercalator, chelator, liposome, antibiotic, vitamin, proteasome inhibitor, anti-oxidant, or reducing agent.

### Claim 5 (depends on 3)

The method of claim 3, wherein the toxicity inducing agent is a metal or salt.

### Claim 6 (depends on 3)

The method of claim 3, wherein the toxicity inducing agent is a compound that causes oxidative stress.

### Claim 7 (depends on 6)

The method of claim 6, wherein the compound that causes oxidative stress is menadione or diamide.

### Claim 8 (depends on 3)

The method of claim 3, wherein the candidate compound is a small organic compound having a molecular weight of more than 50 daltons and less than 750 daltons or a nucleic acid.