Peptide-based Approaches to Directly Target Alpha-Synuclein in Parkinson’s disease

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Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson’s disease and related synucleinopathies. The subsequent formation of toxic, intracellular, Lewy body deposits, in which alpha-synuclein is a major component, is a key diagnostic hallmark of the disease. To reach their therapeutic site of action, peptides must both cross the blood-brain barrier and enter dopaminergic neurons to prevent the formation of these intracellular inclusions. In this review, we describe and summarise the current efforts made in the development of peptides and their mimetics to directly engage with alpha-synuclein with the intention of modulating aggregation, and importantly, toxicity. This is a rapidly expanding field with great socioeconomic impact; these molecules harbour significant promise as therapeutics, or as early biomarkers during prodromal disease stages, or both. As these are age-dependent conditions, an increasing global life expectancy means disease prevalence is rising. No current treatments exist to either prevent or slow disease progression. It is therefore crucial that drugs are developed for these conditions before health care and social care capacities become overrun.
Original languageEnglish
Article number80
Number of pages15
JournalMolecular Neurodegeneration
Issue number1
Early online date9 Nov 2023
Publication statusPublished - 31 Dec 2023

Bibliographical note

Funding and Acknowledgements: JMM LLWS and SGA wish to thank the BBSRC SWBio Doctoral Training Program (BB/T008741/1). JMM and RMM thank Alzheimer’s Research UK for funding (ARUK-PG1018-002 and ARUK-ECRBR2023A-001).

Data Availability: Not applicable.


  • Alpha-Synuclein
  • Parkinson’s Disease
  • Peptide therapeutics
  • Peptidomimetics
  • Synucleinopathies

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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