A Downsized and Optimised Intracellular Library-Derived Peptide Prevents Alpha-Synuclein Primary Nucleation and Toxicity Without Impacting Upon Lipid Binding

Meade, Richard M.; Watt, Kathryn J.C.; Williams, Robert J.; Mason, Jody M.

doi:10.1016/j.jmb.2021.167323

Cited by 10 publications

(12 citation statements)

References 48 publications

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“…The most divergence from the wild-type sequence was observed for positions 1, 6, and 10. From our previous work, alanine at the 6 position resulted in a much improved version of 4554W [e.g., 4554W(N6A)], indicating that modifying these peptides with an additional hydrophobic residue would be advantageous. Moreover, our previous work also showed that the loss of K1 did not result in a loss of efficacy, and this is further supported here by the fact that the screen flips between selecting K and E. Interestingly, the mutation selections (e.g., 46K) were never selected from any of the screens, despite the high conservation of the WT residues.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, each monomeric αS variant (100 μM) was incubated with each PCA peptide winner (100−1000 μM) and DMPS SUVs (200 μM) at 30 °C under quiescent conditions. We also compared the newly identified peptides to our previously optimized version of 4554W−4554W(N6A) 49 as a control and benchmark for future developments.…”

Section: The Peptides Modulate Aggregation Of Theirmentioning

confidence: 99%

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Library-Derived Peptide Aggregation Modulators of Parkinson’s Disease Early-Onset α-Synuclein Variants

Watt

Meade

Williams

et al. 2022

ACS Chem. Neurosci.

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Parkinson’s Disease (PD) is characterized by the accumulation of Lewy bodies in dopaminergic neurons. The main protein component of Lewy bodies, α-synuclein (αS), is also firmly linked to PD through the identification of a number of single point mutations that are autosomal dominant for early-onset disease. Consequently, the misfolding and subsequent aggregation of αS is thought to be a key stage in the development and progression of PD. Therefore, modulating the aggregation pathway of αS is an attractive therapeutic target. Owing to the fact that all but one of the familial mutations is located in the preNAC 45–54 region of αS, we previously designed a semi-rational library using this sequence as a design scaffold. The 45–54 peptide library was screened using a protein-fragment complementation assay approach, leading to the identification of the 4554W peptide. The peptide was subsequently found to be effective in inhibiting primary nucleation of αS, the earliest stage of the aggregation pathway. Here, we build upon this previous work by screening the same 45–54 library against five of the known αS single-point mutants that are associated with early-onset PD (A30P, E46K, H50Q, G51D, and A53T). These point mutations lead to a rapid acceleration of PD pathology by altering either the rate or type of aggregates formed. All ultimately lead to earlier disease onset and were therefore used to enforce increased assay stringency during the library screening process. The ultimate aim was to identify a peptide that is effective against not only the familial αS variant from which it has been selected but that is also effective against WT αS. Screening resulted in five peptides that shared common residues at some positions, while deviating at others. All reduced aggregation of the respective target, with several also identified to be effective at reducing aggregation when incubated with other variants. In addition, our results demonstrate that a previously optimized peptide, 4554W(N6A), is highly effective against not only WT αS but also several of the single-point mutant forms and hence is a suitable baseline for further work toward a PD therapeutic.

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Section: Resultsmentioning

confidence: 99%

Section: The Peptides Modulate Aggregation Of Theirmentioning

confidence: 99%

Library-Derived Peptide Aggregation Modulators of Parkinson’s Disease Early-Onset α-Synuclein Variants

Watt

Meade

Williams

et al. 2022

ACS Chem. Neurosci.

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“…Thus, alternative aggregation-inhibitors have been explored. Among these, we focus on some small peptide-based drugs 82,153,156,213,214 .…”

Section: Small Molecule Drugsmentioning

confidence: 99%

Protein Aggregation-Inhibition: A Therapeutic Route from Parkinson's Disease to Sickle Cell Anemia

Martins

Galamba

2023

Preprint

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Protein aggregation is implicated in multiple diseases, so-called proteinopathies, ranging from neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD) to type 2 diabetes mellitus and sickle cell disease (SCD). The structure of the protein aggregates and the kinetics and mechanisms of aggregation have been the object of intense research over the years toward the development of therapeutic routes, including the design of aggregation inhibitors. Nonetheless, the design of drugs targeting aggregation inhibition remains a challenging endeavor because of multiple, disease-specific factors. Herein, we provide a perspective of this therapeutic route with emphasis on small molecules and peptide-based drugs in two diverse diseases, PD and SCD, aiming at establishing links among proposed aggregation inhibitors. The small and large length-scale regimes of the hydrophobic effect are discussed in light of the importance of hydrophobic interactions in proteinopathies. Some simulation results are reported on model peptides, illustrating the impact of hydrophobic and hydrophilic groups in water's hydrogen-bond network with an impact on drug binding. The seeming importance of aromatic rings and hydroxyl groups in protein-aggregation-inhibitor-drugs is emphasized along with the challenges associated with some inhibitors, limiting their development into effective therapeutic options, and questioning the potential of this therapeutic route.

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“…3, ( 9 )] decreases alpha-synuclein misfolding, aggregation, and toxicity in vitro. 70 Vasoactive intestinal peptide is a major type of peptide having anti-oxidant, anti-inflammatory, neurotropic and neuroprotective activities. This 28 amino-acid bearing molecule exhibits unique potential for the treatment of PD through the modulation of multiple pathways.…”

Section: Peptides In Neurodegenerative Diseasesmentioning

confidence: 99%

Microtubule stabilising peptides: new paradigm towards management of neuronal disorders

Bhargava,

Kulkarni,

Dewangan

et al. 2023

RSC Med. Chem.

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A Downsized and Optimised Intracellular Library-Derived Peptide Prevents Alpha-Synuclein Primary Nucleation and Toxicity Without Impacting Upon Lipid Binding

Cited by 10 publications

References 48 publications

Library-Derived Peptide Aggregation Modulators of Parkinson’s Disease Early-Onset α-Synuclein Variants

Library-Derived Peptide Aggregation Modulators of Parkinson’s Disease Early-Onset α-Synuclein Variants

Protein Aggregation-Inhibition: A Therapeutic Route from Parkinson's Disease to Sickle Cell Anemia

Microtubule stabilising peptides: new paradigm towards management of neuronal disorders

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