Potent chemical chaperone compounds for GM1-gangliosidosis: N-substituted (+)-conduramine F-4 derivatives

MedChemComm ◽  
2015 ◽  
Vol 6 (2) ◽  
pp. 306-310 ◽  
Author(s):  
Shinichi Kuno ◽  
Katsumi Higaki ◽  
Atsushi Takahashi ◽  
Eiji Nanba ◽  
Seiichiro Ogawa
Keyword(s):  
Inhibitory Activity ◽  
Gm1 Gangliosidosis ◽  
Chemical Chaperone ◽  
Chemical Chaperones ◽  
Enzyme Enhancement

The development of chemical chaperones to decrease the inhibitory activity while increasing the enzyme enhancement activity is described.

scholarly journals Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4904
Author(s):  
Gaia Pasqualetto ◽  
Martin Schepelmann ◽  
Carmine Varricchio ◽  
Elisa Pileggi ◽  
Caroline Khogali ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Small Molecules ◽  
Binding Site ◽  
Photoreceptor Cells ◽  
Structural Features ◽  
Outer Cell ◽  
Chemical Chaperone ◽  
Chemical Chaperones ◽  
In Silico Studies ◽  
Leber’S Congenital Amaurosis

Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these conditions is to use opsin-binding compounds as chemical chaperones for opsin. Such molecules have previously shown the ability to aid rhodopsin folding and proper trafficking to the outer cell membranes of photoreceptors. As means to identify novel chemical chaperones for rhodopsin, a structure-based virtual screening of commercially available drug-like compounds (300,000) was performed on the main binding site of the visual pigment chromophore, the 11-cis-retinal. The best 24 virtual hits were examined for their ability to compete for the chromophore-binding site of opsin. Among these, four small molecules demonstrated the ability to reduce the rate constant for the formation of the 9-cis-retinal-rhodopsin complex, while five molecules surprisingly enhanced the formation of this complex. Compound 7, 13, 20 and 23 showed a weak but detectable increase in the trafficking of the P23H mutant, widely used as a model for both retinitis pigmentosa and Leber’s congenital amaurosis, from the ER to the cell membrane. The compounds did not show any relevant cytotoxicity in two different human cell lines, with the only exception of 13. Based on the structures of these active compounds, a series of in silico studies gave important insights on the potential structural features required for a molecule to act either as chemical chaperone or as stabiliser of the 11-cis-retinal-rhodopsin complex. Thus, this study revealed a series of small molecules that represent a solid foundation for the future development of novel therapeutics against these severe inherited blinding diseases.

Lysosomal accumulation of Trk protein in brain of GM1-gangliosidosis mouse and its restoration by chemical chaperone

2011 ◽  
Vol 118 (3) ◽  
pp. 399-406 ◽  
Author(s):  
Ayumi Takamura ◽  
Katsumi Higaki ◽  
Haruaki Ninomiya ◽  
Tomoko Takai ◽  
Junichiro Matsuda ◽  
...  
Keyword(s):  
Gm1 Gangliosidosis ◽  
Chemical Chaperone ◽  
Lysosomal Accumulation

scholarly journals Rescue of Vasopressin V2 Receptor Mutants by Chemical Chaperones: Specificity and Mechanism

2006 ◽  
Vol 17 (1) ◽  
pp. 379-386 ◽  
Author(s):  
J. H. Robben ◽  
M. Sze ◽  
N.V.A.M. Knoers ◽  
P.M.T. Deen
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Level ◽  
Underlying Mechanism ◽  
Cytosolic Calcium ◽  
Cell Surface Expression ◽  
Missense Mutations ◽  
Clinical Value ◽  
Drug Induced ◽  
Chemical Chaperone ◽  
Chemical Chaperones

Because missense mutations in genetic diseases of membrane proteins often result in endoplasmic reticulum (ER) retention of functional proteins, drug-induced rescue of their cell surface expression and understanding the underlying mechanism are of clinical value. To study this, we tested chemical chaperones and sarco(endo)plasmic reticulum Ca2+ ATPase pump inhibitors on Madin-Darby canine kidney cells expressing nine ER-retained vasopressin type-2 receptor (V2R) mutants involved in nephrogenic diabetes insipidus. Of these nine, only V2R-V206D showed improved maturation and plasma membrane rescue with glycerol, dimethyl sulfoxide (DMSO), thapsigargin/curcumin, and ionomycin but not with other osmolytes or growth at 27°C. This revealed that rescue is mutant specific and that this mutant is prone to rescue by multiple compounds. Rescue did not involve changed expression of molecular chaperones calnexin, heat-shock protein (HSP) 70, or HSP90. V2R antagonist SR121463B treatment revealed that V2R-V206D and V2R-S167T were rescued and matured to a greater extent, suggesting that the rescuing activity of a pharmacological versus chemical chaperone is broader and stronger. Calcium measurements showed that rescue of V2R-V206D by thapsigargin, curcumin, and ionomycin was because of increased cytosolic calcium level, rather than decreased endoplasmic reticulum calcium level. The molecular mechanism underlying rescue by DMSO, glycerol, and SR121463B is different, because with these compounds intracellular calcium levels were unaffected.

MLO03 Chemical chaperone therapy: clinical effect in murine GM1-gangliosidosis

2007 ◽  
Vol 11 ◽  
pp. 31
Author(s):  
Y. Suzuki ◽  
S. Ichinomiya ◽  
M. Kurosawa ◽  
M. Ohkubo ◽  
J. Matsuda ◽  
...  
Keyword(s):  
Clinical Effect ◽  
Gm1 Gangliosidosis ◽  
Chemical Chaperone ◽  
Chemical Chaperone Therapy

scholarly journals Chemical Chaperone and Inhibitor Discovery: Potential Treatments for Protein Conformational Diseases

2007 ◽  
Vol 1 ◽  
pp. PMC.S212 ◽  
Author(s):  
Jian-Hua Zhao ◽  
Hsuan-Liang Liu ◽  
Hsin-Yi Lin ◽  
Chih-Hung Huang ◽  
Hsu-Wei Fang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Amyloid Formation ◽  
Loss Of Function ◽  
Chemical Chaperone ◽  
Conformational Diseases ◽  
Chemical Chaperones ◽  
Theoretical Approaches ◽  
Protein Quality Control System

Protein misfolding and aggregation cause a large number of neurodegenerative diseases in humans due to (i) gain of function as observed in Alzheimer's disease, Huntington's disease, Parkinson's disease, and Prion's disease or (ii) loss of function as observed in cystic fibrosis and α1-antitrypsin deficiency. These misfolded proteins could either lead to the formation of harmful amyloids that become toxic for the cells or to be recognized and prematurely degraded by the protein quality control system. An increasing number of studies has indicated that some low-molecular-weight compounds named as chemical chaperones can reverse the mislocalization and/or aggregation of proteins associated with human conformational diseases. These small molecules are thought to non-selectively stabilize proteins and facilitate their folding. In this review, we summarize the probable mechanisms of protein conformational diseases in humans and the use of chemical chaperones and inhibitors as potential therapeutic agents against these diseases. Furthermore, recent advanced experimental and theoretical approaches underlying the detailed mechanisms of protein conformational changes and current structure-based drug designs towards protein conformational diseases are also discussed. It is believed that a better understanding of the mechanisms of conformational changes as well as the biological functions of these proteins will lead to the development and design of potential interfering compounds against amyloid formation associated with protein conformational diseases.

scholarly journals Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Keisuke Kitakaze ◽  
Shusuke Taniuchi ◽  
Eri Kawano ◽  
Yoshimasa Hamada ◽  
Masato Miyake ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Protein Aggregation ◽  
Er Stress ◽  
Chemical Biology ◽  
Chemical Chaperone ◽  
Chemical Chaperones ◽  
Benzothiazole Derivatives ◽  
Chemically Induced ◽  
A Cell

The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. Finally, IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, our data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.

Candidate molecules for chemical chaperone therapy of GM1-gangliosidosis

2013 ◽  
Vol 5 (13) ◽  
pp. 1551-1558 ◽  
Author(s):  
Katsumi Higaki ◽  
Haruaki Ninomiya ◽  
Yoshiyuki Suzuki ◽  
Eiji Nanba
Keyword(s):  
Gm1 Gangliosidosis ◽  
Chemical Chaperone ◽  
Chemical Chaperone Therapy

scholarly journals Chemical chaperone therapy for brain pathology in GM1-gangliosidosis

2003 ◽  
Vol 100 (26) ◽  
pp. 15912-15917 ◽  
Author(s):  
J. Matsuda ◽  
O. Suzuki ◽  
A. Oshima ◽  
Y. Yamamoto ◽  
A. Noguchi ◽  
...  
Keyword(s):  
Brain Pathology ◽  
Gm1 Gangliosidosis ◽  
Chemical Chaperone ◽  
Chemical Chaperone Therapy
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