Challenges in Passive Immunization Strategies to Treat Parkinson Disease

Manfredsson, Fredric P.; Tansey, Malú G.; Golde, Todd E.

doi:10.1001/jamaneurol.2018.0346

Cited by 5 publications

(2 citation statements)

References 9 publications

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“…Additionally, many authors mention that BBB permeability is a significant obstacle to drug discovery. For instance, it has been reported that despite the promising results demonstrated by the humanized monoclonal antibodies against α-synuclein, less than 1% of the antibody crosses the BBB [ 24 ]. Hence, developing more efficient drugs against PD and other diseases from the CNS may consider the BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

Data-Driven Approaches Used for Compound Library Design for the Treatment of Parkinson’s Disease

Barrera-Vázquez

Santiago-de-la-Cruz

Rivero-Segura

et al. 2023

IJMS

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Parkinson’s disease (PD) is the second most common neurodegenerative disease in older individuals worldwide. Pharmacological treatment for such a disease consists of drugs such as monoamine oxidase B (MAO-B) inhibitors to increase dopamine concentration in the brain. However, such drugs have adverse reactions that limit their use for extended periods; thus, the design of less toxic and more efficient compounds may be explored. In this context, cheminformatics and computational chemistry have recently contributed to developing new drugs and the search for new therapeutic targets. Therefore, through a data-driven approach, we used cheminformatic tools to find and optimize novel compounds with pharmacological activity against MAO-B for treating PD. First, we retrieved from the literature 3316 original articles published between 2015–2021 that experimentally tested 215 natural compounds against PD. From such compounds, we built a pharmacological network that showed rosmarinic acid, chrysin, naringenin, and cordycepin as the most connected nodes of the network. From such compounds, we performed fingerprinting analysis and developed evolutionary libraries to obtain novel derived structures. We filtered these compounds through a docking test against MAO-B and obtained five derived compounds with higher affinity and lead likeness potential. Then we evaluated its antioxidant and pharmacokinetic potential through a docking analysis (NADPH oxidase and CYP450) and physiologically-based pharmacokinetic (PBPK modeling). Interestingly, only one compound showed dual activity (antioxidant and MAO-B inhibitors) and pharmacokinetic potential to be considered a possible candidate for PD treatment and further experimental analysis.

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Section: Discussionmentioning

confidence: 99%

Data-Driven Approaches Used for Compound Library Design for the Treatment of Parkinson’s Disease

Barrera-Vázquez

Santiago-de-la-Cruz

Rivero-Segura

et al. 2023

IJMS

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“…NCT02157714 (completed) 4) Phase I in healthy individuals. NCT02095171 (completed) Aggregated α-syn at C-terminal around aa 122, supposedly aa 118–126 (suggested by preclinical data of E94) VH CDR1 : SISSGGGSTYYPDNVKG VH CDR1 : GGAGIDY VL CDR1 : KSIQTLLYSSNQKNYLA VL CDR2 : WASIRKS VL CDR3 : QQYYSYPL IgG1 n/a n/a Humanized version of murine 9E4 antibody [ 58 , 65 , 69 , 70 , 71 , 89 , 109 , 113 , 115 , 116 , 117 ] …”

Section: Introductionmentioning

confidence: 99%

Alpha-synuclein Immunization Strategies for Synucleinopathies in Clinical Studies: A Biological Perspective

et al. 2022

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The therapeutic strategies currently available for neurodegenerative diseases such as Parkinson’s disease target only the symptoms of the disease. Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy can be summarized as synucleinopathies, as they are all characterized by the aggregation and accumulation of alpha-synuclein (α-syn) in the brain. Targeting α-syn by its formation and progression opens a new and promising disease-modifying therapeutic strategy. Thus, several distinct immunotherapeutic approaches are currently being evaluated in clinical trials. The objective of this article is to review, from a biological perspective, the most important properties of these passive and active immunotherapies to point out their relevance and suitability for the treatment of synucleinopathies.

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