Target-Templated Construction of Functional Proteomimetics Using Photo-Foldamer Libraries.

Area of Science:

• Chemical Biology
• Drug Discovery
• Proteomics

Background:

• Proteomimetic engineering traditionally relies on structure-based design.
• Challenging protein targets often lack detailed surface characterization, hindering traditional methods.

Purpose of the Study:

• To develop a new strategy for constructing proteomimetics against difficult protein targets without prior structural data.
• To enable efficient mapping of protein-protein interaction sites and facilitate proteomimetic ligand development.

Main Methods:

• Utilized a 100-member photoreactive foldamer library as local surface mimetics.
• Employed systems chemistry for affinity maturation of initial binding 'hits'.
• Applied diazirine-based photo-crosslinking to identify binding sites on target proteins like STAT3 and K-Ras.

Main Results:

• Identified key interactions driven by surface-oriented proteinogenic side chains.
• Successfully mapped functionally relevant protein interfaces, allosteric sites, and unexplored regions on STAT3 and oncogenic K-Ras.
• Achieved a two-orders-of-magnitude affinity improvement through target-templated dynamic linking of foldamers.
• Developed a dimeric K-Ras ligand exhibiting protein-like catalytic functions.

Conclusions:

• The photo-foldamer approach enables efficient mapping of protein-protein interaction sites.
• This method provides a viable starting point for proteomimetic ligand development, bypassing the need for a priori structural hypotheses.
• The strategy is effective even for shallow and dynamic protein surface patches.