Structure-based drug design identifies polythiophenes as antiprion compounds

Area of Science:

• Neuroscience
• Biochemistry
• Materials Science

Background:

• Prion diseases, or transmissible spongiform encephalopathies, are fatal neurodegenerative disorders with no current treatments.
• Prions are misfolded, aggregated forms of the cellular prion protein (PrP(Sc)) that cause disease.

Purpose of the Study:

• To investigate the antiprion properties of luminescent conjugated polythiophenes (LCPs).
• To identify structural requirements for LCPs to bind and stabilize prion aggregates.
• To design and test optimized LCPs for prion disease treatment.

Main Methods:

• Administration of diverse LCP libraries to prion-infected mouse brains via osmotic minipumps.
• Solid-state nuclear magnetic resonance (ssNMR) and molecular dynamics (MD) simulations to analyze LCP-prion interactions.
• Design and synthesis of new LCPs based on identified structural rules.

Main Results:

• Antiprion activity required LCPs with at least five thiophene rings and regularly spaced carboxyl side groups.
• Anionic LCP side chains interacted with cationic residues on model prions.
• Optimized LCPs demonstrated significant prophylactic and therapeutic efficacy in mice, extending survival by >80%.
• Lead LCP compound showed activity against both mouse and hamster prions and efficacy upon intraperitoneal administration.

Conclusions:

• Established structure-activity relationships for LCPs targeting prion aggregates.
• Demonstrated the feasibility of rational chemical design for antiprion compounds.
• Highlighted the potential of LCPs as a therapeutic strategy for prion diseases and other protein aggregation disorders.