α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

Abstract

Abstractα-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of α-helical peptides that bind to these α-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into a high anti-aggregation potency and the ability to abrogate oligomer-induced cell damage. Using a structure-guided search we identify a human peptide expressed in the brain and the gastrointestinal tract with analogous binding, anti-aggregation, and detoxifying properties. The chemical entities we describe here may represent a therapeutic avenue for the synucleinopathies and are promising tools to assist diagnosis by discriminating between native and toxic α-synuclein species.

Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies

“…These stable oligomers have been reported to represent good models to investigate the structural and biological properties of prefibrillar amyloid oligomers as they are homologous to the transiently populated parallel β-sheet oligomers that are formed during fibril formation through heterogeneous nucleation at the typical conditions used for in vitro fibril formation (air/water interface under shaking conditions) [ 54 , 56 ]. However, not all the properties are similar or homologous, as the kinetically trapped nature of these species implies that they are deficient in elongating [ 57 ], in contrast to the transient parallel β-sheet oligomers, which are consequently difficult to trap.…”

“…In addition, these approaches can potentially cross-react with monomers if they are associated with vesicles, or other protein complexes. In this context, molecules that can bind specifically the toxic species of αSyn, even under conditions of a large excess of monomeric protein [ 56 ], can be very useful for developing diagnostic tools.…”

“…αSyn oligomers can induce neurotoxicity in a variety of ways and can be propagated from cell to cell, properties that have made the scientific community to consider them as key players in the aetiology of synucleionopathies. Given that a primary event of oligomer toxicity involves perturbation of neuronal membranes, a number of molecules and strategies have been designed to target the interaction of oligomers with these cellular structures, which, indeed, have been reported to elicit beneficial effects in different cellular and animal models [56,[92][93][94][95][96][97]. Some of these molecules are being tested as potential therapeutic agents.…”

Peptide-Based Vaccines for Neurodegenerative Diseases: Recent Endeavors and Future Perspectives

“…Additional approaches against neurodegenerative diseases have been recently reported, which often use specific peptides to target neurotoxic aggregates, e.g., of Aβ or α-syn [48,49]; though these approaches are out of the scope of the present paper, we briefly refer here to humanin (HN), as an indicative example of neurotherapeutic peptides that may prevent Aβ aggregation. HN is a 24-mer peptide [50], probably of mitochondrial origin.…”

Unzipping the Secrets of Amyloid Disassembly by the Human Disaggregase

“…For instance, trodusquemine, a naturally-occurring aminosterol, can not only inhibit primary and secondary aggregation processes [129], but also effectively suppresses the toxicity of α-syn and Aβ oligomers [129,130]. Similarly, several α-helical peptidic scaffolds have been found to abrogate oligomer-induced cell damage without interfering with the native function of α-syn [131]. These compounds could avoid the deleterious impact of the disaggregases, neutralizing the toxic, seed-competent species released during the disassembly process.…”