Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Abstract

The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson’s disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson’s disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson’s. Likewise, molecules that target alpha-synuclein could alter the disease pathway that leads to Parkinson’s and may serve as first-in class therapeutics compared to existing treatment options such as levodopa and dopamine agonist that do not necessarily modify the disease pathway. Notwithstanding the promising benefits that alpha-synuclein presents to therapeutics and diagnostics development for Parkinson’s disease, finding ways to address potential challenges such as inadequate preclinical models, safety and efficacy will be paramount to achieving clinical translation. In this comprehensive review paper, we described the role of alpha-synuclein in the pathogenesis of Parkinson’s disease, as well as how its structure and function relationship delineate disease onset and progression. We further discussed different alpha-synuclein-based diagnostic modalities including biomolecular assays and molecular imaging. Finally, we presented current small molecules and biologics that are being developed as disease-modifying drugs or positron emission tomography imaging probes for Parkinson’s disease.

Synthesis and Preliminary Characterization of Putative Anle138b-Centered PROTACs against α-Synuclein Aggregation

“…Reactions were monitored by TLC on silica gel, using UV light at 254 nm as a direct detection method, or by charring either with a phosphomolybdic acid ethanolic solution, with a potassium permanganate solution or with a ninhydrin solution. 1 H-NMR and 13 C-NMR spectra were recorded in either acetone-d6, CDCl 3 , CD 3 OD, DMSO-d6, or pyridine-d5, depending on compounds' solubility, on Bruker DRX-400 and Bruker DRX-300 instruments. Chemical shifts (δ) for proton and carbon signals are quoted relatively to tetramethylsilane as an internal standard and expressed in parts per million (ppm).…”

“…Therefore, small molecule αSyn binders able to inhibit its oligomerization and aggregation and, therefore, reduce its toxicity, have become a focus for the scientific community [ 13 ].…”

Unconventional protein secretion (UPS): role in important diseases

“…In addition, another UPS protein, a-synuclein, has been identified as a putative biomarker of neurodegeneration associated with PD. Molecules that target a-synuclein may thus serve as therapeutics, possible advantages to present options such as levodopa and dopamine agonists [ 102 ].…”

Development of Pyridothiophene Compounds for PET Imaging of α‐Synuclein

“…[3,4] In α-synucleinopathies, αsyn forms insoluble aggregates which are stabilized by a ßsheet structure. [5,6] In PD and LBD, these aggregates are found in neuronal cell bodies (Lewy bodies) as well as axons and dendrites (Lewy neurites), with their distribution depending on the disease type and state. In MSA, the α-syn aggregates present as filamentous inclusions in oligodendrocytes (glia cell inclusions).…”