Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.
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.
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.
Yixuan
Y
Zeng
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.
Wenyuan
W
Guo
Department of Rehabilitation, The First Affiliated Hospital, Guangzhou, Guangdong, People's Republic of China.
Guangqing
G
Xu
Key laboratory on Assisted Circulation, Ministry of Health, Department of Cardiovascular Medicine of the First Affiliated Hospital, Guangzhou, Guangdong, People's Republic of China.
Qinmei
Q
Wang
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.
Luyang
L
Feng
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.
Simei
S
Long
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.
Fengyin
F
Liang
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.
Yi
Y
Huang
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.
Xilin
X
Lu
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
Shichang
S
Li
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
Jiebin
J
Zhou
Swiss Huntington's Disease Center, Department of Neurology, University of Bern, Bern, Switzerland.
Jean-Marc
JM
Burgunder
School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
Jiyan
J
Pang
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.
Zhong
Z
Pei
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000071058:Huntingtin Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D062105:Molecular Docking Simulation; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects* / Q000235:genetics; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000071058:Huntingtin Protein; D018696:Neuroprotective Agents; D066329:Protein Aggregates; D011714:Pyrans; D054852:Small Molecule Libraries; C515343:xyloketal B
Caenorhabditis elegans; Huntington’s disease; molecular target; mutant Huntingtin; protein misfolding; xyloketal derivatives