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Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.

Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, Liang F, Huang Y, Lu X, Li S, Zhou J, Burgunder JM, Pang J, Pei Z - Drug Des Devel Ther (2016)

Bottom Line: Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases.Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds.Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangzhou Center, Chinese Huntington's Disease Network, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT
Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

No MeSH data available.


Related in: MedlinePlus

Effect of xyloketal derivatives on stressed life span and motility in the C. elegans Huntingotn’s diseasea model.Notes: (A) Survival analysis of worms treated by compounds (or DMSO as negative control) using the Kaplan-Meier method. The life span curve shows a time-dependent cumulative survival rate. The average survival time was: 1 (6.91 h**), 2 (6.86 h**), 3 (8.00 h**), 4 (6.50 h**), 5 (7.96 h**), 6 (6.79 h**), DMSO (5.05 h) respectively. (B) Bending frequency analysis was measured by the bending behavior over 20 s of worms in M9 buffer and was accomplished by ANOVA. The average bending counts were: 1 (28.5**), 2 (32.1**), 3 (32.1**), 4 (26.5**), 5 (31.4**), 6 (28.3**), DMSO (23.3). **P<0.001.Abbreviations:C. elegans, Caenorhabditis elegans; HD, Huntington’s disease; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance.
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f3-dddt-10-1443: Effect of xyloketal derivatives on stressed life span and motility in the C. elegans Huntingotn’s diseasea model.Notes: (A) Survival analysis of worms treated by compounds (or DMSO as negative control) using the Kaplan-Meier method. The life span curve shows a time-dependent cumulative survival rate. The average survival time was: 1 (6.91 h**), 2 (6.86 h**), 3 (8.00 h**), 4 (6.50 h**), 5 (7.96 h**), 6 (6.79 h**), DMSO (5.05 h) respectively. (B) Bending frequency analysis was measured by the bending behavior over 20 s of worms in M9 buffer and was accomplished by ANOVA. The average bending counts were: 1 (28.5**), 2 (32.1**), 3 (32.1**), 4 (26.5**), 5 (31.4**), 6 (28.3**), DMSO (23.3). **P<0.001.Abbreviations:C. elegans, Caenorhabditis elegans; HD, Huntington’s disease; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance.

Mentions: As expected, Q148 worms displayed a clear phenotype, providing a suitable model to examine the potential anti-mHtt toxin properties of xyloketals. All the Q148 model worms exposed to xyloketal compounds 1–6 showed marked improvement in the bioactivity assays; all six derivatives prolonged the life span under stress and improved motility (Figure 3A and B).


Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.

Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, Liang F, Huang Y, Lu X, Li S, Zhou J, Burgunder JM, Pang J, Pei Z - Drug Des Devel Ther (2016)

Effect of xyloketal derivatives on stressed life span and motility in the C. elegans Huntingotn’s diseasea model.Notes: (A) Survival analysis of worms treated by compounds (or DMSO as negative control) using the Kaplan-Meier method. The life span curve shows a time-dependent cumulative survival rate. The average survival time was: 1 (6.91 h**), 2 (6.86 h**), 3 (8.00 h**), 4 (6.50 h**), 5 (7.96 h**), 6 (6.79 h**), DMSO (5.05 h) respectively. (B) Bending frequency analysis was measured by the bending behavior over 20 s of worms in M9 buffer and was accomplished by ANOVA. The average bending counts were: 1 (28.5**), 2 (32.1**), 3 (32.1**), 4 (26.5**), 5 (31.4**), 6 (28.3**), DMSO (23.3). **P<0.001.Abbreviations:C. elegans, Caenorhabditis elegans; HD, Huntington’s disease; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance.
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f3-dddt-10-1443: Effect of xyloketal derivatives on stressed life span and motility in the C. elegans Huntingotn’s diseasea model.Notes: (A) Survival analysis of worms treated by compounds (or DMSO as negative control) using the Kaplan-Meier method. The life span curve shows a time-dependent cumulative survival rate. The average survival time was: 1 (6.91 h**), 2 (6.86 h**), 3 (8.00 h**), 4 (6.50 h**), 5 (7.96 h**), 6 (6.79 h**), DMSO (5.05 h) respectively. (B) Bending frequency analysis was measured by the bending behavior over 20 s of worms in M9 buffer and was accomplished by ANOVA. The average bending counts were: 1 (28.5**), 2 (32.1**), 3 (32.1**), 4 (26.5**), 5 (31.4**), 6 (28.3**), DMSO (23.3). **P<0.001.Abbreviations:C. elegans, Caenorhabditis elegans; HD, Huntington’s disease; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance.
Mentions: As expected, Q148 worms displayed a clear phenotype, providing a suitable model to examine the potential anti-mHtt toxin properties of xyloketals. All the Q148 model worms exposed to xyloketal compounds 1–6 showed marked improvement in the bioactivity assays; all six derivatives prolonged the life span under stress and improved motility (Figure 3A and B).

Bottom Line: Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases.Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds.Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Disease, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Guangzhou Center, Chinese Huntington's Disease Network, Guangzhou, Guangdong, People's Republic of China.

ABSTRACT
Huntington's disease is an autosomal-dominant neurodegenerative disorder, with chorea as the most prominent manifestation. The disease is caused by abnormal expansion of CAG codon repeats in the IT15 gene, which leads to the expression of a glutamine-rich protein named mutant Huntingtin (Htt). Because of its devastating disease burden and lack of valid treatment, development of more effective therapeutics for Huntington's disease is urgently required. Xyloketal B, a natural product from mangrove fungus, has shown protective effects against toxicity in other neurodegenerative disease models such as Parkinson's and Alzheimer's diseases. To identify potential neuroprotective molecules for Huntington's disease, six derivatives of xyloketal B were screened in a Caenorhabditis elegans Huntington's disease model; all six compounds showed a protective effect. Molecular docking studies indicated that compound 1 could bind to residues GLN369 and GLN393 of the mutant Htt protein, forming a stable trimeric complex that can prevent the formation of mutant Htt aggregates. Taken together, we conclude that xyloketal derivatives could be novel drug candidates for treating Huntington's disease. Molecular target analysis is a good method to simulate the interaction between proteins and drug compounds. Further, protective candidate drugs could be designed in future using the guidance of molecular docking results.

No MeSH data available.


Related in: MedlinePlus