Identification of Broad-Spectrum Inhibitors Targeting Multiple Amyloidogenic Proteins Using Functional Group-Based...

Area of Science:

• Biochemistry
• Pharmacology
• Drug Discovery

Background:

• Amyloidosis involves protein misfolding and aggregation into toxic fibrils.
• A conserved fibril structure suggests pan-amyloid therapeutics targeting multiple proteins are feasible.

Purpose of the Study:

• To identify small molecules that bind to multiple amyloidogenic proteins.
• To validate a functional group-based screening approach for multitarget drug discovery.

Main Methods:

• Screened 10,272 small molecules against four amyloidogenic proteins: amyloid β, serum amyloid A1, islet amyloid polypeptide, and transthyretin.
• Identified five critical functional groups for high-affinity binding.
• Performed functional group-based screening to find pan-amyloid binding compounds.

Main Results:

• Five functional groups were identified as crucial for binding to all four target proteins.
• A workflow for functional group-driven screening was validated.
• Efficient identification of candidate pan-amyloid binding compounds was achieved.

Conclusions:

• Functional group-based screening is effective for multitarget drug discovery in amyloidosis.
• This strategy facilitates the development of novel pan-amyloid therapeutics.
• Findings offer insights into targeting diverse amyloidogenic proteins simultaneously.