Photoreactive synthetic regulator of protein function and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9334231-B2
Application number	US-201514626124-A
Country	US
Kind code	B2
Filing date	Feb 19, 2015
Priority date	Oct 31, 2008
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

The present disclosure provides a photoreactive synthetic regulator of protein function. The present disclosure further provides a light-regulated polypeptide that includes a subject synthetic regulator. Also provided are cells and membranes comprising a subject light-regulated polypeptide. The present disclosure further provides methods of modulating protein function, involving use of light.

First claim

What is claimed is:

1. A compound having the formula:
(A) n -X 1 -(B) m -X 2 -(C) p
wherein
A is a polypeptide association moiety selected from hydrogen, C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, —NR 10 R 11 , —NR 12 C(O)R 13 , C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, C 6-20 aryl, substituted C 6-20 aryl, heteroaryl, heterocyclic, heterocyclooxy, heterocyclothio, heteroarylamino, heterocycloamino, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, substituted C 4-10 cycloalkenyl, cyano, halo, —OR 10 , —C(O)OR 10 , —SR 10 , —S(O)R 10 , —S(O) 2 R 10 ;
wherein
R 10 and R 11 are independently selected from hydrogen and C 1-10 alkyl;
R 12 is hydrogen or C 1-10 alkyl; and
R 13 is selected from hydrogen, C 1-10 alkyl, C 1-8 alkenyl, C 6-10 aryl, and substituted C 1-10 alkyl;

B is a photoisomerizable group comprising an azobenzene;
C is a ligand selected from an agonist, an antagonist, an allosteric modulator, and a blocker;
n is 1;
each of m and p is independently an integer from 1 to 10; and
X 1 and X 2 are each an optional spacer independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, and aminoacyl.

2. The compound of claim 1 , wherein the polypeptide association moiety comprises a group selected from C 1 -C 10 alkyl, substituted C 1 -C 10 alkyl, and —NR 10 R 11 , wherein R 10 and R 11 are independently selected from hydrogen and C 1-10 alkyl.

3. The compound of claim 1 , wherein the polypeptide association moiety comprises —NR 10 R 11 , wherein each of R 10 and R 11 are hydrogen.

4. The compound of claim 1 , wherein the polypeptide association moiety comprises —NR 10 R 11 , wherein each of R 10 and R 11 are C 1-10 alkyl.

5. The compound of claim 1 , wherein the polypeptide association moiety comprises —NR 10 R 11 , wherein each of R 10 and R 11 are methyl.

6. The compound of claim 1 , wherein the polypeptide association moiety comprises a substituted C 1 -C 10 alkyl.

7. The compound of claim 1 , wherein the polypeptide association moiety comprises a C 1 -C 10 alkyl with one or more halogen substituents.

8. The compound of claim 1 , wherein the polypeptide association moiety comprises a C 1 -C 10 alkyl with one or more fluoro substituents.

9. The compound of claim 1 , wherein the polypeptide association moiety comprises a methyl with one or more halogen substituents.

10. The compound of claim 1 , wherein the polypeptide association moiety comprises a methyl with one or more fluoro substituents.

11. The compound of claim 1 , wherein each of n, m, and p is one.

12. The compound of claim 1 , wherein the ligand is a ligand for an ion channel.

13. The compound of claim 12 , wherein the ion channel is a sodium channel, a potassium channel, a calcium channel, or a chloride channel.

14. The compound of claim 1 , wherein the ligand is selected from an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor agonist, a GABA A receptor ligand, and a transient receptor potential cation channel, subfamily V, member 1 (TRPV 1 ) ligand.

15. The compound of claim 1 , wherein the compound is a compound of Formula XII:

wherein
x is 1;
y is 1;
R 1 is —NR 10 R 11 ;
R 2 is hydrogen;
R 3 , R 4 , and R 5 are each independently C 2-8 alkyl;
R 6 is hydrogen;
R 10 is C 1-10 alkyl;
R 11 is substituted C 1-10 alkyl; and

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 , wherein:
R 3 , R 4 , and R 5 are each C 3 alkyl;
R 10 is C 2 alkyl; and
R 11 is methyl substituted with an aryl.

17. The compound of claim 16 , wherein R 11 is methyl substituted with phenyl.

18. The compound of claim 15 , wherein:
R 3 , R 4 , and R 5 are each C 4 alkyl;
R 10 is C 2 alkyl; and
R 11 is methyl substituted with an aryl.

19. The compound of claim 18 , wherein R 11 is methyl substituted with phenyl.

20. The compound of claim 15 , wherein:
R 3 , R 4 , and R 5 are each C 2 alkyl;
R 10 is C 2 alkyl; and
R 11 is methyl substituted with substituted aryl.

21. The compound of claim 20 , wherein R 11 is methyl substituted with substituted phenyl.

22. The compound of claim 1 , wherein the compound is a compound of Formula XI:

wherein
Q 1 is —C(═O)—;
Q 2 is NR 3 R 4 ;
R 3 and R 4 are each C 2 alkyl;
R 1 is —NR 10 R 11 ;
x is 1;
y is 1;
R 2 is hydrogen;
R 6 is hydrogen;
R 10 is C 2 alkyl; and
R 11 is methyl substituted with aryl;

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , wherein:
A is an —NR 10 R 11 group;
R 10 is C 1-10 alkyl;
R 11 is substituted C 1-10 alkyl;
B is a photoisomerizable group comprising an azobenzene;
C is a ligand selected from an agonist, an antagonist, an allosteric modulator, and a blocker;
each of n, m, and p is 1; and
X 1 and X 2 are each an optional spacer independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, and aminoacyl.

24. The compound of claim 23 , wherein R 11 is methyl substituted with aryl.

25. The compound of claim 24 , wherein R 11 is methyl substituted with phenyl.

26. The compound of claim 23 , wherein R 10 is C 2 alkyl.

27. The compound of claim 23 , wherein the ligand is a ligand for an ion channel.

28. The compound of claim 27 , wherein the ion channel is a sodium channel, a potassium channel, a calcium channel, or a chloride channel.

Assignees

• Univ California

Inventors

• Trauner Dirk
• Isacoff Ehud Y
• Kramer Richard H
• Banghart Matthew R
• Fortin Doris L
• Mourot Alexandre

Classifications

• C07C245/08 Primary

  with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene · CPC title

• C12Q1/025

  for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics (antimicrobial activity C12Q1/18) · CPC title

• G01N33/5008

  for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• G01N33/566

  using specific carrier or receptor proteins as ligand binding reagents {where possible specific carrier or receptor proteins are classified with their target compounds} · CPC title