Discovery of SHANK1-PDZ Peptide-Fragment Inhibitors Using a Dynamic Ligation Screening Strategy.

Area of Science:

• Chemical Biology
• Drug Discovery
• Structural Biology

Background:

• Targeting protein-protein interactions (PPIs) is crucial in drug discovery.
• Methods for targeting β-strand-mediated PPIs are less developed than those for α-helix-mediated PPIs.
• PDZ domains, involved in β-strand-mediated PPIs, present a challenging target due to their unique binding motif.

Purpose of the Study:

• To develop novel ligands that mimic β-strands for targeting PPIs.
• To explore fragment-based approaches for designing ligands against PDZ domains.
• To identify fragments that bind to the SHANK1-PDZ domain.

Main Methods:

• Utilized a peptide-based template and replaced segments with target/structure-agnostic fragments.
• Employed reversible hydrazone exchange reactions for fragment identification and screening.
• Investigated the binding affinity of identified fragments to the SHANK1-PDZ domain.

Main Results:

• Identified fragments at both C- and N-termini of a PDZ recognition motif with affinity for SHANK1-PDZ.
• Observed negative co-operativity when combining two different fragments into single ligands.
• Demonstrated the utility of the acylhydrazone-fragment approach for screening PDZ-binding ligands.

Conclusions:

• The fragment-based approach is effective for β-strand mimicry and designing ligands for PDZ domains.
• The developed workflow offers a versatile strategy for future drug discovery efforts targeting other protein interactions.
• This study broadens the scope of acylhydrazone-fragment chemistry in chemical biology.