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Review
. 2021 Oct;11(10):3015-3034.
doi: 10.1016/j.apsb.2021.02.016. Epub 2021 Feb 26.

Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Kai Zhang  1 , Shiou Zhu  1 , Jiamei Li  1 , Tingting Jiang  1 , Lu Feng  1 , Junping Pei  1 , Guan Wang  1   2 , Liang Ouyang  1 , Bo Liu  1
Affiliations
Review

Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Kai Zhang et al. Acta Pharm Sin B. 2021 Oct.

Abstract

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.

Keywords: 3-MA, 3-methyladenine; 5-HT2A, Serotonin 2A; 5-HT2C, serotonin 2C; A2A, adenosine 2A; AADC, aromatic amino acid decarboxylase; ALP, autophagy-lysosomal pathway; AMPK, 5ʹAMP-activated protein kinase; ATG, autophagy related protein; ATP13A2, ATPase cation transporting 13A2; ATTEC, autophagosome-tethering compound; AUC, the area under the curve; AUTAC, autophagy targeting chimera; Autophagy; BAF, bafilomycinA1; BBB, blood−brain barrier; CL, clearance rate; CMA, chaperone-mediated autophagy; CNS, central nervous system; COMT, catechol-O-methyltransferase; DA, dopamine; DAT, dopamine transporter; DJ-1, Parkinson protein 7; DR, dopamine receptor; ER, endoplasmic reticulum; ERRα, estrogen-related receptor alpha; F, oral bioavailability; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GBA, glucocerebrosidase β acid; GWAS, genome-wide association study; HDAC6, histone deacetylase 6; HSC70, heat shock cognate 71 kDa protein; HSPA8, heat shock 70 kDa protein 8; IMPase, inositol monophosphatase; IPPase, inositol polyphosphate 1-phosphatase; KI, knockin; LAMP2A, lysosome-associated membrane protein 2 A; LC3, light chain 3; LIMP-2, lysosomal integrated membrane protein-2; LRRK2, leucine-rich repeat sequence kinase 2; LRS, leucyl-tRNA synthetase; LUHMES, lund human mesencephalic; Lamp2a, type 2A lysosomal-associated membrane protein; MAO-B, monoamine oxidase B; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; MYCBP2, MYC-binding protein 2; NMDA, N-methyl-d-aspartic acid; ONRs, orphan nuclear receptors; PD therapy; PD, Parkinson's disease; PDE4, phosphodiesterase 4; PI3K, phosphatidylinositol 3-kinase; PI3P, phosphatidylinositol 3-phosphate; PINK1, PTEN-induced kinase 1; PLC, phospholipase C; PREP, prolyl oligopeptidase; Parkin, parkin RBR E3 ubiquitin−protein ligase; Parkinson's disease (PD); ROS, reactive oxygen species; SAR, structure–activity relationship; SAS, solvent accessible surface; SN, substantia nigra; SNCA, α-synuclein gene; SYT11, synaptotagmin 11; Small-molecule compound; TFEB, transcription factor EB; TSC2, tuberous sclerosis complex 2; Target; ULK1, UNC-51-like kinase 1; UPS, ubiquitin−proteasome system; mAChR, muscarinic acetylcholine receptor; mTOR, the mammalian target of rapamycin; α-syn, α-synuclein.

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Conflict of interest statement

The authors have no conflicts of interest to declare.

Figures

Image 1
Graphical abstract
Figure 1
Figure 1
The relationship between autophagy and PD: the mutations of casual genes cause some ALP defects and further lead to key pathological states. ALP dysfunction is one of the important pathogenesis of PD. Pharmacologically induced autophagy can rescue the pathological states to a certain extent and play a neuroprotective role.
Figure 2
Figure 2
Several pharmacological interventions are available to induce cytoautophagy at the nucleation, elongation, fusion, or degradation phase. The figure shows the key targets and representative small-molecule compounds in autophagic regulatory pathways.
Figure 3
Figure 3
(A) The structures of compounds targeting AMPK. (B) The structure–activity relationship (SAR) of A-769662 and GSK621.
Figure 4
Figure 4
The structures of compounds targeting mTOR.
Figure 5
Figure 5
(A) The structure optimization process of BL-918. (B) The structures of compounds targeting IMPase.
Figure 6
Figure 6
(A) An overview of ATP binding site of LRRK2 (PDB:6VP6). The kinase is illustrated with dark blue ribbons, and the key amino acid residues are depicted in black solid lines. (B) The SAR of aminopyrimidine derivatives LRRK2 inhibitors. (C) The structures of compounds 25−27.
Figure 7
Figure 7
The structures of compounds targeting beclin-1.
Figure 8
Figure 8
(A) Curcumin and its analogues replaced the β-diketone part. (B) The structures of trehalose and XCT790. (C) The structures of compounds targeting GCase.
Figure 9
Figure 9
(A) The structures of compounds targeting c-ABL. (B) The discovery and structure optimization process of imatinib and nilotinib. (C) The interaction modes of imatinib and nilotinib with c-ABL (PDB:2OIQ,3CS9). The key amino acid residues are illustrated with pink, and imatinib and nilotinib are depicted in blue and yellow respectively. The hydrogen bonds are shown in black dashed lines.
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