Peptide-based approaches to directly target alpha-synuclein in Parkinson's disease

Abstract

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.

Keywords: Alpha-Synuclein; Parkinson’s Disease; Peptide therapeutics; Peptidomimetics; Synucleinopathies.

Fig. 1

αS aggregation into Lewy bodies in PD and regions of interest. Top: In PD, alpha-synuclein (αS) is able to aggregate, via oligomers, into protofibrils, fibrils and Lewy bodies, leading to the death of dopaminergic neurons in the substantia nigra pars compacta region of the brain, which ultimately results in PD symptoms. Also shown is an aggregation profile in which the lag-phase, exponential phase and stationary phases are shown along with corresponding species of αS known to form. Figure created with BioRender.com. Bottom: the primary structure of αS is shown divided into three distinct regions. (1) Amphipathic N-terminal region (residues 1–60) containing seven imperfect repeats of the KTKEGV sequence and where most familial mutations linked to early-onset PD are found [62]. (2) NAC (non-amyloid component) domain, a central hydrophobic region (residues 61–95) involved in protein aggregation. (3) A negatively charged and proline-rich C-terminal region (residues 96–140). Point-mutations linked to early onset-PD (A30P/G, E46K, H50Q, G51D, A53T/E/V respectively) are shown in red for reference. Also shown are peptide sequence identifiers (green) corresponding to compounds in Table 1 and where within αS, and/or the aggregation pathway, that they are thought to target and impact