Tethering cysteine residues using cyclic disulfides
Described herein are compounds and methods for tethering proteins. For example, dimers of proteins, including SOD1 and DJ-1, are described, where the dimers are formed by the covalent bonding of a cysteine on the first monomer to a cysteine on the second monomer via a cyclic disulfide linker. The covalently attached dimers exhibit increased stabilization.
1 . A method of treating a subject suffering from Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, or Alzheimer's disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, wherein
the compound of Formula I is
wherein
Y is S, S═O, or S(═O) 2 ;
n is 0, 1, 2, 3, or 4; and
R is independently selected from the group consisting of —H, —OH, —NH 2 , —NHR′, —N(R′) 2 , alkyl, —OMs, —OTs, —OTf, and —CO 2 H; or any two geminal R groups, taken together, form an imine; or any two vicinal R groups, taken together, form a ring; wherein any alkyl or imine may be substituted with a carbamide, a carboxylate, or a hydroxyl.
2 . The method of claim 1 , wherein the compound is selected from the group consisting of
3 . A method of treating a subject suffering from Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, or Alzheimer's disease, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula II, wherein the compound of Formula II is
wherein
R″ is-H, alkyl, or aryl, or both R″, taken together, form a ring; wherein any alkyl, aryl, or ring may be substituted with-OH, alkyl, or halo.
4 . The method of claim 3 , wherein the compound is
5 . The method of claim 1 , wherein the compound is
6 . The method of claim 1 , wherein the compound is
7 . The method of claim 1 , wherein the compound is
8 . The method of claim 1 , wherein the compound is
9 . The method of claim 1 , wherein the compound is
10 . The method of claim 1 , wherein the compound is
11 . The method of claim 1 , wherein the compound is
12 . The method of claim 1 , wherein the compound is
13 . The method of claim 1 , wherein the compound is
14 . The method of claim 1 , wherein the compound is
15 . The method of claim 1 , wherein the compound is
16 . The method of claim 7 , wherein said subject is suffering from Amyotrophic Lateral Sclerosis (ALS).
17 . The method of claim 7 , wherein said subject is suffering from Parkinson's disease.
18 . The method of claim 7 , wherein said subject is suffering from Alzheimer's disease.