A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion.

A glimpse into the structural properties of α-synuclein oligomers.

α-Synuclein (αS) aggregation is the main neurological hallmark of a group of debilitating neurodegenerative disorders, collectively referred to as synucleinopathies, of which Parkinson's disease is the most prevalent. αS oligomers formed during the initial stages of aggregation are considered key pathogenic drivers of disease onset and progression, standing as privileged targets for therapeutic intervention and diagnosis. However, the structure of αS oligomers and the mechanistic basis of oligomer to fibril conversion are yet poorly understood, thereby precluding the rational formulation of strategies aimed at targeting oligomeric species.

aSynPEP-DB: a database of biogenic peptides for inhibiting α-synuclein aggregation.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, yet effective treatments able to stop or delay disease progression remain elusive. The aggregation of a presynaptic protein, α-synuclein (aSyn), is the primary neurological hallmark of PD and, thus, a promising target for therapeutic intervention. However, the lack of consensus on the molecular properties required to specifically bind the toxic species formed during aSyn aggregation has hindered the development of therapeutic molecules.

PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties.

The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities.