IP Library › Granted Patent US 9,551,721

Granted Patent B2

US 9,551,721 · App. 12/791,389 · Granted Jan 24, 2017

Identification of small molecules recognized by antibodies in subjects with neurodegenerative diseases

Inventors: Muralidhar Reddy Moola (Jupiter, FL); Dwight German (Dallas, TX); Steven Connell (McKinney, TX); Rosemary Wilson (Jupiter, FL); Johnnie Wilson (Jupiter, FL); Thomas Kodadek (Jupiter, FL)

Assignees: The Board of Regents of the University of Texas System; OPKO Health, Inc.

G01N33/6896 G01N33/564 G01N33/6845 G01N2800/2821 G01N2800/2835

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Quick Facts

Patent No.: US 9,551,721
App. No.: 12/791,389
Granted: Jan 24, 2017
Kind: B2

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Abstract

The present invention provides for the identification of individuals having neurodegenerative diseases (ND). Peptoids recognized by Parkinson's Disease- and Alzheimer's Disease-specific antibodies are identified, allowing one to diagnose or predict ND in subjects.

Claims (348)

1. A method of detecting antibodies in an antibody-containing sample from a patient suspected of or having a neurodegenerative disease comprising:

(a) contacting an antibody-containing sample with a support having affixed thereto a peptoid having a formula selected from:

(i) the formula (1A):

wherein,

R 1 is independently selected from C 1-6 alkyl or C 2-6 alkenyl or C 1-6 alkyl substituted with —OH or NH 2 or —COOH; or piperonyl or C 1-3 alkylphenyl;

R 2 is C 1-3 alkylphenyl;

R 3 is C 1-3 alkylphenyl;

R 4 is independently selected from C 1-6 alkyl or C 2-6 alkenyl or C 1-6 alkyl substituted with —OH or NH 2 or —COOH; or piperonyl or C 1-3 alkylphenyl;

R 5 is C 1-4 alkyl substituted with —OH or NH 2 ; or

(ii) formula (1B):

wherein

R 6 is independently selected from C 2-6 alkenyl, C 1-6 alkyl independently and optionally substituted with —OH, NH 2 or —COOH; piperonyl or C 1-6 alkylphenyl;

R 7 is independently selected from C 2-6 alkenyl, C 1-6 alkyl independently and optionally substituted with —OH, NH 2 or —COOH; piperonyl;

R 8 is independently selected from C 2-6 alkenyl, C 1-6 alkyl independently and optionally substituted with —OH, NH 2 or —COOH; piperonyl; or

(iii) formula (1C):

wherein

R 9 , R 11 and R 13 are independently selected from C 2-6 alkenyl, C 1-6 alkyl independently and optionally substituted with —OH, NH 2 or —COOH; piperonyl or C 1-6 alkylphenyl;

R 10 is piperonyl;

R 12 is C 1-6 alkyl substituted with —OH, NH 2 or —COOH;

R 14 is C 1-6 alkyl substituted with —OH, NH 2 or —COOH; or

(iv) formula (1D):

wherein,

R 17 is independently selected from the group consisting of C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 18 is selected from C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 19 is selected from C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 20 is selected from C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 21 is selected from C 1-6 alkylphenyl;

R 22 is selected from C 1-6 alkylphenyl;

R 23 is selected from C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 24 is selected from C 1-6 alkyl substituted with —OH, NH 2 or —COOH;

n is 1; or

for a compound of formula 1D,

R 17 is C 2-6 alkenyl;

R 18 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 19 is piperonyl;

R 20 is C 2-6 alkenyl;

R 21 is C 2-6 alkenyl;

R 22 is C 2-6 alkenyl;

R 23 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 24 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

n is 1; or for a compound of formula 1D,

R 17 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 18 is piperonyl;

R 19 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 20 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 21 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 22 is C 1-6 alkylphenyl;

R 23 is C 1-6 alkyl optionally substituted with —OH, NH 2 or —COOH;

R 24 is C 1-6 alkyl substituted with —OH, NH 2 or —COOH;

n is 1;

wherein L is an optional linker moiety, M is a substrate or support; and m, n, o, and/or p, unless specified, is 0-6, and wherein Z is a functional group capable of coupling to a linker, substrate, or a label; and

(b) detecting antibodies bound to said peptoid,

wherein antibodies bound to said peptoid are indicative of a neurodegenerative disease in said subject.

2. The method of claim 1 , further comprising obtaining said sample from a subject suspected of having Parkinson's disease or Alzheimer's disease and comparing the results of said sample to the results obtained from a control sample from non-diseased patients.

3. The method of claim 2 , further comprising making a diagnosis of Alzheimer's Disease for a subject from which said sample was obtained if antibody binding to said peptoid is greater than that observed for said control non-diseased patients.

4. The method of claim 1 , wherein said sample is contacted with more than one peptoid of claim 1 .

5. The method of claim 4 , wherein said sample is contacted with a compound of formula:

6. The method of claim 1 , wherein said support is a bead, a plate, a dipstick, a filter, a membrane a pin, or a well.

7. The method of claim 1 , wherein said sample is blood, serum, saliva or CSF.

8. The method of claim 1 , wherein detecting comprises RIA, FIA, ELISA, Western blot, flow cytometry, FRET, or surface plasmon resonance.

9. A method of detecting antibodies in an antibody-containing sample from a patient suspected of or having a neurodegenerative disease comprising:

(a) contacting an antibody-containing sample with a support having affixed thereto a peptoid having a formula selected from, wherein the peptoid has the formula:

wherein A-I indicate the structure is as shown or modified as follows:

Replacement

Amine Position

Amine Side Chain, NH 2 R (Ref. No.)

D, E

n-Bu 1

D, E

s-Bu

—Cy

A, B, G

—CH 2 CH 2 —CH(Ph) 2

A, B, G

—CH 2 Ph

C, F, H

—CH 2 CH 2 OH

C, F, H

—OH

A, B, G

C, F, H

H, I

A, B, G

C, F, H

-i-Bu

—CH 2 Cy

C, F, H

A, B, G

—CH 2 OClPh

A, B, G

—CH 2 pOCH 3 Ph

A, B, G

—CHCH 3 Ph

C, F, H

—CH 2 CH 2 CH 2 NHBoc

A, B, G

C, F, H

—CH 2 CH 2 OMe

C, F, H

—CH 2 CH 2 CH 2 OH

C, F, H

—CH(CH 3 )CH 2 OH

C, F, H

—CH 2 CHOHCH 2 OH

A, B, G

—CH 2 CH(OH)Ph

A, B, G

A, B, G, C, F, G

A, B, G

C, F, G

A, B, G

C, F, H

A, B, D, E, G

A, B, G, C, F, H

C, F, H

-nPr

C, F, H

A, B, G

C, F, H

—CH 2 CH 2 CH 2 OMe

A, B, C, D, E, F, G, H

C, F, H

A, B, G

A, B, C, F, G, H

A, B, G

C, F, G

C, F, H, I

C, F, H

A, B, G

G, A, B

A, B, G

C, F, H, I

A, B, G

C, F, H

C, F, H, I

A, B, G

—CH 3

A, B, C, F, G, H

Is C, F or H

A, B, G

C, F, H

—CH 2 CH 2 OH

A, B, G

A, B, G, C, F, H

A, B, G

A, B, D, E, G

D, E

A, B, G

C, F, H

A, B, G

A, B, D, E, G

A, B, G

A, B, G, C, F, G

A, B, G

C, F, H

D, E

A, B, G

C, F, H

A, B, G

D, E

A, B, G, D, E

A, B, G

C, F, H

A, B, G

C, F, H

A, B, G

and wherein Z is a functional group capable of coupling to a linker, substrate, or a label; and

(b) detecting antibodies bound to said peptoid.

10. The method of claim 9 , wherein the peptoid has the formula:

wherein Z is a functional group capable of coupling to a linker, substrate, or a label.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 24, 2011

From: MOOLA, REDDY; WILSON, ROSEMARY; WILSON, JOHNNIE; KODADEK, THOMAS; GERMAN, DWIGHT; CONNELL, STEVEN

To: THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM; OPKO HEALTH, INC.

Reel/Frame 025862/0864 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 12, 2010

From: MOOLA, REDDY; GERMAN, DWIGHT; CONNELL, STEVEN; WILSON, ROSEMARY; WILSON, JOHNNIE; KODADEK, THOMAS

To: THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

Reel/Frame 024827/0375 →

CONFIRMATORY LICENSE Recorded Jun 21, 2010

From: UNIVERSITY OF TEXAS SW MED CTR/DALLAS

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 024564/0064 →

Continuity (3)

Provisional Application 61183260 · Jun 2, 2009

Provisional Application 61318655 · Mar 29, 2010

Related Publication 20100303805A1 · Dec 2, 2010