Unconventional Secondary Structure Mimics: Ladder-Rungs

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Protein-protein interactions are crucial in cellular processes.
• Mimicking these interactions is a key strategy in drug discovery.
• Secondary structures, like sheets, offer potential binding sites.

Purpose of the Study:

• To design and synthesize a novel chemotype capable of mimicking protein-protein interfaces.
• To investigate the binding of this chemotype to the urokinase plasminogen activator receptor (uPAR).
• To evaluate the cellular effects of the chemotype on cell invasion, migration, and wound healing.

Main Methods:

• Bioinformatics analysis to identify suitable structural motifs for mimicry.
• Chemical synthesis of a novel hydantoin triazole chemotype (1).
• Biophysical assays to confirm binding to uPAR.
• Cellular assays to assess effects on invasion, migration, and wound healing.

Main Results:

• Bioinformatics revealed the chemotype aligns well with protein-protein interfaces, particularly parallel and antiparallel sheets.
• The synthesized chemotype (1) successfully bound to uPAR.
• The compound demonstrated significant effects on cellular invasion, migration, and wound healing processes.

Conclusions:

• The novel hydantoin triazole chemotype effectively mimics protein-protein interactions at the uPA⋅uPAR interface.
• Targeting uPAR with this chemotype offers a potential therapeutic strategy for modulating cell behavior.
• This approach holds promise for developing new treatments for conditions involving aberrant cell invasion, migration, and wound healing.