Covalent modulators show promise for targeting misfolded β-amyloid, tau, and α-synuclein in neurodegenerative diseases

Neurodegenerative diseases like Alzheimer's and Parkinson's are characterized by the accumulation of misfolded protein aggregates, such as β-amyloid, tau, and α-synuclein. These aggregates, particularly early-stage oligomers, are highly neurotoxic and drive disease progression. Current therapeutic strategies struggle to effectively target these "undruggable" misfolded monomers at early stages, limiting neuroprotective efficacy. A critical gap exists for interventions that can prevent initial protein misfolding and aggregation.

This review systematically outlines covalent modulators designed to target protein misfolding and aggregation in neurodegenerative diseases. It synthesizes current advances in strategies that interact directly with early-stage misfolded monomers and oligomers. The authors focused on modulators affecting key proteins: β-amyloid, tau, α-synuclein, and superoxide dismutase 1. The aim was to highlight their potential as valuable pharmacological tools and therapeutic candidates.

The review identified and categorized various covalent modulators that target specific functional nucleophilic residues within disordered proteins. These modulators demonstrate potential to overcome the "undruggability" challenge of misfolded monomers by directly interacting at early aggregation stages. The authors emphasized that preventing aggregation at early stages is crucial for achieving significant neuroprotective efficacy. The reviewed strategies target major misfolded proteins implicated in neurodegenerative diseases, including β-amyloid, tau, α-synuclein, and superoxide dismutase 1 (SOD1). This approach aims to halt the progression of the amyloid cascade by preventing the formation of toxic aggregates.

The core finding is that covalent approaches offer an "intriguing opportunity" for early antiaggregant therapeutic intervention, particularly against neurotoxic oligomer intermediates.