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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

Structure of xyloketal B and compounds 1–6.
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f1-dddt-10-1443: Structure of xyloketal B and compounds 1–6.

Mentions: The marine environment often provides a sink for the discovery of many novel, natural, and active compounds. Xyloketal B, an extract from marine mangrove fungi,9 has exhibited potent neuroprotection in different models of neurological diseases, including Parkinson’s disease and epilepsy.10–13 Xyloketal B has unique bicyclic acetal moieties fused to its aromatic core structure (Figure 1), which can be easily modified to improve and expand its activity.5,14 Given that some xyloketal derivatives have the ability to hydrogen bond, xyloketal may have the potential to bind to mHtt proteins and disrupt the process of Htt aggregation, thereby attenuating the pathological progression of HD.


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)

Structure of xyloketal B and compounds 1–6.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835117&req=5

f1-dddt-10-1443: Structure of xyloketal B and compounds 1–6.
Mentions: The marine environment often provides a sink for the discovery of many novel, natural, and active compounds. Xyloketal B, an extract from marine mangrove fungi,9 has exhibited potent neuroprotection in different models of neurological diseases, including Parkinson’s disease and epilepsy.10–13 Xyloketal B has unique bicyclic acetal moieties fused to its aromatic core structure (Figure 1), which can be easily modified to improve and expand its activity.5,14 Given that some xyloketal derivatives have the ability to hydrogen bond, xyloketal may have the potential to bind to mHtt proteins and disrupt the process of Htt aggregation, thereby attenuating the pathological progression of HD.

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