A Chemical Chaperone‐Based Drug Candidate is Effective in a Mouse Model of Amyotrophic Lateral Sclerosis (ALS)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons and skeletal muscle atrophy. The majority of ALS cases are acquired spontaneously, with inherited disease accounting for only 10 % of all cases. Recent studies provide compelling evidence that aggregates of misfolded proteins underlie both types of ALS. Small molecules such as artificial chaperones can prevent or even reverse the aggregation of proteins associated with various human diseases. However, their very high active concentration (micromolar range) severely limits their utility as drugs. We synthesized several ester and amide derivatives of chemical chaperones. The lead compound 14, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N-dimethylpropan-1-amine oxide shows, in the micromolar concentration range, both neuronal and astrocyte protective effects in vitro; at daily doses of 10 mg kg(-1) 14 improved the neurological functions and delayed body weight loss in ALS mice. Members of this new chemical chaperone derivative class are strong candidates for the development of new drugs for ALS patients.

Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target

“…The protective effect exerted by TMAO as a chemical chaperone has also been observed in other diseases, such as Machado-Joseph disease/spinocerebellar ataxia-3 (MJD/SCA-3) [ 85 ] and amyotrophic lateral sclerosis (ALS) [ 86 ]. On one hand, MJD/SCA-3 is an inherited neurodegenerative disorder where the truncated form of mutated ataxin-3 causes aggregation and cell death in vitro and in vivo.…”

“…However, the major limitation in using chemical chaperones like TMAO as drugs is their very active concentration, in the millimolar range. Because of that, Getter et al [ 86 ] designed a lipophilic derivative of TMAO, which was able to improve neurological functions in mice, preventing ER-stress-induced apoptosis of NSC-34 motor neuron-like cells and primary mouse astrocytes.…”

Astaxanthin-based polymers as new antimicrobial compounds

“…Upon completion of incubation, a standard MTT test was performed. 24 pATX-coated microtitre plates 96-well polypropylene plates were coated by dispensing 150 µl of polymeric solution (10% w/v in THF) into the wells. 25 The plates were left in the dark and the solvent was evaporated at room temperature in a fume hood.…”

“…The peaks at δ 5.53 ppm were assigned to hydrogen atoms 2,35 (CH-group) in the ATX unit and the ,15,17,18,20,22,23,24,26,27,28,30, at the ATX's polyene fragment. The peaks at δ 1.22, 1.24-1.41 ppm were assigned to hydrogen atoms 7,8,41,42 (CH3-group) in the ATX unit.…”

Chemical Chaperones Modulate the Formation of Metabolite Assemblies

“…Chemical chaperones were shown to reduce endoplasmic reticulum stress, correct the misfolded form of the p53 tumor suppressor protein and restore glucose homeostasis [13][14][15][16][17]. The effect of different chemical chaperones in ameliorating protein misfolding in neurodegenerative and prion diseases has been well documented both in vitro and in vivo [18][19][20][21][22][23][24][25]. Chemical chaperones thus could potentially serve as scaffolds for the development of novel therapeutics for protein misfolding diseases.…”