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Generation, optimization and characterization of novel anti-prion compounds
Andrea Altieri1, Evgeny A Spiridonov2, Semen I Sivtzev2
1Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, 1-3, Moscow 119991, Russian Federation; EDASA Scientific, Via Stingi 37, San Salvo 66050, Italy.
Bioorganic & Medicinal Chemistry
|October 16, 2020
Summary
Researchers explored novel analogues of an anti-prion compound to understand Structure Activity Relationships (SARs). Two compounds showed a 10-fold improvement in anti-prion activity and good cell viability.
Area of Science:
- Neuroscience
- Biochemistry
- Medicinal Chemistry
Background:
- Prions are misfolded proteins implicated in neurodegenerative diseases.
- These diseases pose significant risks to veterinary and public health.
- Understanding Structure Activity Relationships (SARs) is crucial for developing effective anti-prion therapeutics.
Purpose of the Study:
- To explore the chemical space around the anti-prion compound BB 0300674.
- To elucidate the Structure Activity Relationships (SARs) of novel anti-prion agents.
- To identify new compounds with enhanced anti-prion activity and favorable safety profiles.
Main Methods:
- Synthesis of 43 novel analogues based on four distinct chemical clusters.
- Biological screening of synthesized compounds against PrPSc and mutant PrP toxicity assays.
- Evaluation of cell viability for promising anti-prion candidates.
Main Results:
- Two novel compounds, designated 59 and 65, demonstrated a 10-fold increase in anti-prion activity compared to the lead compound BB 0300674.
- These compounds exhibited promising cell viability, indicating a potentially favorable safety profile.
- The study successfully mapped key SARs for this class of anti-prion agents.
Conclusions:
- The identified compounds (59 and 65) represent significant advancements in anti-prion drug discovery.
- Further investigation into these analogues could lead to novel therapeutic strategies for prion diseases.
- This SAR exploration provides a foundation for the rational design of next-generation anti-prion drugs.
