A new MAP-Rasagiline conjugate reduces α-synuclein inclusion formation in a cell model

被引:11
|
作者
Vale, Nuno [1 ,2 ,3 ,4 ]
Alves, Claudia [5 ]
Sharma, Vaishali [6 ]
Lazaro, Diana F. [6 ]
Silva, Sara [1 ,2 ,3 ]
Gomes, Paula [5 ]
Outeiro, Tiago Fleming [6 ,7 ,8 ]
机构
[1] Univ Porto, Fac Pharm, Dept Drug Sci, Lab Pharmacol, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto, Portugal
[2] Univ Porto IPATIMUP, Inst Mol Pathol & Immunol, Rua Julio Amaral de Carvalho 45, P-4200135 Porto, Portugal
[3] Univ Porto, i3S, Rua Alfredo Allen 208, P-4200135 Porto, Portugal
[4] Univ Porto, Inst Biomed Sci Abel Salazar ICBAS, Dept Mol Pathol & Immunol, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto, Portugal
[5] Univ Porto, Fac Sci, Dept Chem & Biochem, LAQV REQUIMTE, Rua Campo Alegre 687, P-4169007 Porto, Portugal
[6] Univ Med Ctr Gottingen, Dept Expt Neurodegenerat, Ctr Biostruct Imaging Neurodegenerat, Ctr Nanoscale Microscopy & Mol Physiol Brain, Gottingen, Germany
[7] Max Planck Inst Expt Med, Gottingen, Germany
[8] Newcastle Univ, Med Sch, Inst Neurosci, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
关键词
Alpha-synuclein; Cell-penetrating peptides; Lewy bodies; Parkinson's disease; Rasagiline; PARKINSONS-DISEASE; PENETRATING PEPTIDES; DOPAMINERGIC-NEURONS; DELIVERY; INHIBITOR; FUSION;
D O I
10.1007/s43440-019-00032-x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background Parkinson's disease (PD) is the second most common neurodegenerative disease of the elderly. Current therapies are only symptomatic, and have no disease-modifying effect. Therefore, disease progresses continuously over time, presenting with both motor and non-motor features. The precise molecular basis for PD is still elusive, but the aggregation of the protein alpha-synuclein (alpha-syn) is a key pathological hallmark of the disease and is, therefore, a major focus of current research. Considering the intrinsic properties of cell-penetrating peptides (CPPs) for mediating drug delivery of neurotherapeutics across the blood brain barrier (BBB), these might open novel opportunities for the development of new solutions for the treatment of brain-related aspects of PD and other neurodegenerative disorders. Methods Here, we synthesized solid-phase CPPs using an amphipathic model peptide (MAP) conjugated with the drug Rasagiline (RAS), which we named RAS-MAP, and evaluated its effect on alpha-syn inclusion formation in a human cell-based model of synucleinopathy. Results We found that treatment with RAS-MAP at low concentrations (1-3 mu M) reduced alpha-syn aggregation in cells. Conclusions For the first time, we report that conjugation of a current drug used in the therapy of PD with CPP reduces alpha-syn aggregation, which might prove beneficial in PD and other synucleinopathies.
引用
收藏
页码:456 / 464
页数:9
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