Photoreactive synthetic regulator of protein function and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016229794-A1
Application number	US-201615132553-A
Country	US
Kind code	A1
Filing date	Apr 19, 2016
Priority date	Oct 31, 2008
Publication date	Aug 11, 2016
Grant date	—

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 synthetic regulator of polypeptide function, the regulator having the formula: (A) n -X 1 -(B) m -X 2 -(C) p , wherein
A is a polypeptide association moiety; B is a photoisomerizable group; C is a ligand; each of n, m, and p is independently an integer from 1 to 10; X 1 , when present, is a spacer; and X 2 , when present, is a spacer.

2 . The regulator of claim 1 , wherein the ligand is an agonist, an antagonist, an allosteric modulator, or a blocker.

3 . The regulator of claim 1 , wherein the photoisomerizable group comprises a moiety selected from an azobenzene, a fulgide, a spiropyran, a triphenyl methane, a thioindigo, a diarylethene, and an overcrowded alkene.

4 . The regulator of claim 1 , wherein the photoisomerizable group comprises an azobenzene.

5 . The regulator of claim 1 , wherein the polypeptide association moiety comprises a group 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;
R 13 is selected from hydrogen, C 1-10 alkyl, C 1-8 alkenyl, C 6-10 aryl, and substituted C 1-10 alkyl.

6 . The regulator of claim 1 , wherein the polypeptide association moiety comprises a group selected from hydrogen, C 1-10 alkyl, substituted C 1-10 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, C 1-10 alkyl, substituted C 1-10 alkyl, 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, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, and substituted C 4-10 cycloalkenyl;
R 12 is selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, C 6-10 aryl, substituted C 6-20 aryl, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, and substituted C 4-10 cycloalkenyl; and
R 13 is selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, C 6-10 aryl substituted C 6-20 aryl, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, substituted C 4-10 cycloalkenyl, CH 2 —N(CH 2 CH 3 ) 3 + , and —CH 2 —SO 3 − .

7 . The regulator of claim 1 , wherein the polypeptide association moiety comprises a group selected from hydrogen, alkyl, amino, substituted amino, and aminoacyl.

8 . The regulator of claim 1 , wherein each of n, m, and p is one.

9 . The regulator of claim 1 , wherein X 1 and X 2 are independently selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, and aminoacyl.

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

wherein Q 1 is —CH 2 — or —C(═O)—;
Q 2 is

each of R 1 are independently selected from hydrogen, C 1-10 alkyl, substituted C 1-10 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 ;
x is an integer from 1 to 5;
y is an integer front 1 to 4;
R 2 is selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, 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, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, and substituted C 4-10 cycloalkenyl;
R 3 , R 4 , and R 5 are independently selected from hydrogen, C 2-8 alkyl, substituted C 2-10 alkyl, 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, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, and substituted C 4-10 cycloalkenyl;
each of R 6 are independently selected from hydrogen, C 1 -C 10 alkyl, substituted C 1-10 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 ;
R 10 and R 11 are independently selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, 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, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, and substituted C 4-10 cycloalkenyl;
R 12 is selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, 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, C 4-10 cycloalkyl, substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, and substituted C 4-10 cycloalkenyl;
R 13 is selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 2-10 alkynyl, substituted C 2-10 alkynyl, C 6 -C 10 aryl, substituted C 6-20 aryl, C 4-10 substituted C 4-10 cycloalkyl, C 4-10 cycloalkenyl, substituted C 4-10 cycloalkenyl, —CH 2 —N(CH 2 CH 3 ) 3 + , and —CH 2 —SO 3 − ;
or a pharmaceutically acceptable salt thereof.

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

wherein
each of R 1 are independently selected from hydrogen, C 1-10 alkyl, substituted C 1-10 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 ,

Assignees

• Univ California

Inventors

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

Classifications

• C09B44/04 Primary

  from coupling components containing amino as the only directing group · 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

• G01N33/566

  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

• G01N33/5008

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

• G01N2500/00

  Screening for compounds of potential therapeutic value · CPC title