Discovery of SHANK1-PDZ Peptide-Fragment Inhibitors Using a Dynamic Ligation Screening Strategy
Year: 2026
Type: article
Abstract: The development of ligands that modulate protein-protein interactions (PPIs) remains an ongoing challenge in chemical biology and drug discovery. While several approaches have been elaborated to target α-helix-mediated PPIs, methods for β-strand-mediated PPIs are less well developed. In addition to the shallow and extended interfaces characteristic of PPIs, β-strand-mediated PPIs exhibit topographical complexity, with side chains oriented above and below the plane of the strand, alongside hydrogen-bond donor and acceptor groups oriented perpendicular to the side chains. One class of β-strand-mediated PPIs involves the structurally conserved PDZ domains, which recognize protein partners through a β-strand containing a short consensus motif; canonical PDZ binding motifs (PBMs) recognize their substrates through a C-terminal carboxylate, offering a particularly challenging motif to mimic. Peptides and peptidomimetics represent a promising template for the design of ligands that target β-strand-mediated PPIs. In this work, we replaced segments of a peptide-based template using target/structure-agnostic fragments to achieve β-strand mimicry. Using reversible hydrazone exchange reactions allowed us to identify fragments at both the C- and N-terminus of an internal PDZ recognition motif with affinity for the SHANK1-PDZ domain. When combined into ligands bearing two different fragments, negative co-operativity was observed. In addition to broadening the acylhydrazone-fragment approach to screen for PDZ-binding ligands, this workflow for successive screening and combination of fragments should have broader applicability to other targets in future.
Source: Biochemistry
Institutions: University of Leeds, University of Birmingham
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: Deciphering the function of intrinsically disordered protein regions in a cellular context, Coiled-coil Technology for Regulating Intracellular Protein-protein Interactions, A Platform for Chemical Probe Identification and Optimization Facilitating Interrogation of Biological Mechanisms, Coiled-coil Technology for Regulating Intracellular Protein-protein Interactions, Deciphering the function of intrinsically disordered protein regions in a cellular context
OpenAlex ID: W7151462970