A triosmium carbonyl cluster that inhibits α-synuclein aggregation and disassembles preformed aggregates

Area of Science:

• Organometallic Chemistry
• Neuroscience
• Drug Discovery

Background:

• Alpha-synuclein aggregation is a critical pathological hallmark of Parkinson's disease (PD).
• Developing effective inhibitors of alpha-synuclein aggregation is a key therapeutic goal for PD.
• Osmium carbonyl clusters represent a novel class of compounds with potential neuroprotective properties.

Purpose of the Study:

• To investigate the potential of two triosmium carbonyl clusters, Os3(μ-H)(μ-SC6H4-p-NO2)(CO)10 (1) and Os3(μ-H)(kO,μ-O'-2-flavone)(CO)9 (2), as inhibitors of alpha-synuclein aggregation.
• To evaluate the efficacy and safety profiles of these clusters in Parkinson's disease models.

Main Methods:

• Synthesis and characterization of triosmium carbonyl clusters 1 and 2.
• In vitro assays to assess the inhibition of alpha-synuclein aggregation using wild-type and A53T-mutant forms.
• Evaluation of the ability of the clusters to disassemble pre-formed alpha-synuclein aggregates.
• Assessment of the safety profile of the most effective cluster.

Main Results:

• Both clusters 1 and 2 effectively inhibited alpha-synuclein aggregation in both wild-type and A53T-mutant models.
• Cluster 2 exhibited superior inhibitory efficacy compared to cluster 1.
• Cluster 2 demonstrated a significantly better safety profile.
• Cluster 2 was also capable of disassembling pre-formed alpha-synuclein aggregates.

Conclusions:

• Triosmium carbonyl clusters, particularly cluster 2, show significant potential as therapeutic agents for Parkinson's disease by targeting alpha-synuclein aggregation.
• Cluster 2's dual action of inhibiting aggregation and disassembling existing aggregates, coupled with its favorable safety profile, makes it a promising candidate for further development.