Will Targeting Alpha-Synuclein Lead to Treatments for Parkinson’s Disease?

α-Synuclein is the principal constituent of the main neuropathological characteristic of Parkinson's disease. α-Synuclein is a protein that is abundant in neurons and localized in vicinity to presynaptic terminals. As a matter of fact, α-synuclein aggregates and forms insoluble fibrils in the dopaminergic neurons, which causes dysfunction in the release of neurotransmitters, critical for the normal brain function.

Thus, α-synuclein has emerged as a major target in Parkinson's disease and other related conditions known as synucleinopathies. Researchers have been studying the role of α-synuclein to determine how this protein may influence Parkinson's disease and Lewy body dementia (LBD). LBD encompasses the two related clinical diagnoses of Parkinson's disease dementia and dementia with Lewy bodies¹What is LBD? Lewy Body Dementia Association 2019. Among candidates in the drug development pipeline, there are several different approaches for α-synuclein targeted therapeutics including reducing extracellular α-synuclein, blocking the misfolding of α-synuclein, preventing α-synuclein aggregation, and curtailing α-synuclein synthesis. α-Synuclein exists in several structural forms and researchers have identified that reducing the formation and propagation of β-sheet oligomers could be a route for therapeutic intervention²J.M. Froula et al. J. Bio. Chem., 294, 10392-10406 (2019). Several drug candidates targeting α-synuclein are known to be in the early stages of drug development from preclinical to Phase II as shown in Figure 1.

Figure 1 Estimated Number of alpha-Synuclein Targeted Drug Candidates by Development Stage (Source: GlobalData)

The current pipeline of α-synuclein targeted therapies consists of small molecules, antibodies, proteins and peptides, antisense oligonucleotides, and gene therapies. To achieve reduction of extracellular α-synuclein, passive therapies such as the administration of prepared antibodies and active immunization using synthetic peptides are under development. Examples of clinical programs include NPT200-11, a small molecule inhibitor of α-synuclein misfolding, ANVS-401 (Posiphen), an inhibitor of α-synuclein synthesis, and ENT-01, a small molecule drug candidate that prevents the aggregation of α-synuclein by stabilizing conformations of α-synuclein that are incapable of assembling into toxic pore-like oligomers in cell membranes³GlobalData 2021.

Parkinson's disease results from a complex combination of genetic and environmental factors. Yet their respective influence on the disease initiation could likely vary from one individual to another. Consequently, therapeutic strategies for preventing or slowing disease progression might be more efficient, if personalized to each case. With our strong expertise and leading position as peptides manufacturer, we offer a large selection of peptides, amino acid derivatives, and biochemicals. Our innovative peptides portfolio includes a variety of sequence modifications, and salt forms, as well as established bioactive peptides used in different applications such as Parkinson's disease and multiple sclerosis research.

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