Chemical chaperonins as novel molecular modulators of beta protein aggregation present in conformational diseases
This invention relates to chemistry and biochemistry applied to the field of medicine and is referred to a new method of prevention and therapeutic treatment of conformational diseases (CD), in particular to amyloid origin diseases by administrating an effective amount of one or more compounds, salts, prodrugs or solvates, which are considered herein as chemical chaperonins, of Formula I, Where: R 1 : -alkylenyl-C(O)NH-alkylenyl-R 3 , -alkylenyl-C(O)O—R 4 ; R 3 : —COOH, —OH, —SH, —NH 2 , —NH-alkyl-, —NH-dithiocarbamate-alkyl, —N-alkyl-dithiocarbamate alkaline earth metal salts. R 4 : succinimidyl group. R 2 : —H, -alkyl; wherein the term “alkyl” is characterized by a linear or branched aliphatic chain, hydrogen and saturated carbon atoms, comprising a methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl groups. Wherein, the term “alkylenyl” refers to a divalent analog of a linear or branched alkyl group, preferably ethylenyl (—CH 2 CH 2 —) or butylenyl (—CH 2 CH 2 CH 2 CH 2 —) radicals. These compounds are neutral, lipophilic, and have low molecular weight. The present invention provides a novel method for CD prevention and therapeutic treatment, by inhibition, reduction and breakdown of prefibril, protofibril, amyloid fiber and plaque structures, all of them characterized by presenting cross-β-toxic structures (e.g. Alzheimer disease (AD), Parkinson's disease (PD), Diabetes Mellitus Type II (DM2), etc.), through the administration of the Formula I compounds, which are considered herein as chemical chaperonins, in any acceptable pharmaceutical composition of one or more compounds or salts thereof, prodrug or solvate, that are capable of inhibiting, reducing, removing, etc., the formation of these structures which cause a protein misfolding, as well as to disaggregate fibers already formed.
1. A method for reducing the cytotoxic effect of a β-folded amyloidegenic protein comprising:
adding a chaperonin with respect to a β-folded amyloidegenic protein, said chaperonin comprises a compound of Formula I;
wherein; R 1 : -alkylenyl-C(O)NH-alkylenyl-R 3 , -alkylenyl-C(O)O—R 4 ;
R 3 : —COOH, —OH, —SH, —NH 2 , —NH-alkyl-, —NH-dithiocarbamate-alkyl, —N-alkyl-dithiocarbamate alkaline earth metal salts; or salts of the above listed groups, pharmaceutically acceptable, for the treatment of an amyloidegenic disease;
R 4 : succinimidyl group; and
R 2 : —H, -alkyl.
2. The method of claim 1 , wherein (a) further comprising inhibiting, reducing and refolding under controlled acceleration and/or disaggregation of soluble oligomers, prefibrilar, protofibril and fiber structures and amyloid plaques.
3. The method of claim 1 , wherein Formula I further comprises: N 1 -(2-aminoethyl)-N 4 -(1-naphthyl) succinimide, methyl(2-{[4-(1-naphthylamino)-4-xobutanoyl]amino}ethyl)dithiocarbamate, N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine, 6-{[4-(1-naphthylamino)-4-oxobutanoyl]amino}hexanoic acid, N 3 ,N 3′ -butane-1,4-bis(N 1 -1-naftilsuccinamida)N 1 -(2-aminobutyl)-N 4 -(1-naphthyl) succinimide or salts, prodrugs or pharmaceutically acceptable solvates thereof.
4. The method of claim 1 , wherein the disease is one selected from Diabetes mellitus (type II), Alzheimer's disease, Parkinson's Disease, Huntington's Disease, and Transmissible Spongiform Encephalopathies.
5. The method of claim 1 , wherein (a) further comprises preventing the formation of soluble oligomers, prefibril, protofibril and fiber structures and amyloid plaques.
6. The method of claim 1 , further comprising reducing the cytotoxic effect of a β-folded structure present in the disease.
7. A method for cytotoxic protection of cerebellar granule cells (CGC) comprising:
(a) providing a chaperonin with respect to a protein, said chaperonin comprises a compound of Formula I;
wherein; R 1 : -alkylenyl-C(O)NH-alkylenyl-R 3 , -alkylenyl-C(O)O—R 4 ;
R 3 : —COOH, —OH, —SH, —NH 2 , —NH-alkyl-, —NH-dithiocarbamate-alkyl, —N-alkyl-dithiocarbamate alkaline earth metal salts; or salts of the above listed groups, pharmaceutically acceptable, for the treatment of an amyloidegenic disease;
R 4 : succinimidyl group; and
R 2 : —H, -alkyl.