Identification of β-strand mediated protein-protein interaction inhibitors using ligand-directed fragment ligation.

ABSTRACT: β-Strand mediated protein-protein interactions (PPIs) represent underexploited targets for chemical probe development despite representing a significant proportion of known and therapeutically relevant PPI targets. β-Strand mimicry is challenging given that both amino acid side-chains and backbone hydrogen-bonds are typically required for molecular recognition, yet these are oriented along perpendicular vectors. This paper describes an alternative approach, using GKAP/SHANK1 PDZ as a model and dynamic ligation screening to identify small-molecule replacements for tranches of peptide sequence. A peptide truncation of GKAP functionalized at the N- and C-termini with acylhydrazone groups was used as an anchor. Reversible acylhydrazone bond exchange with a library of aldehyde fragments in the

SUBMITTER: Hegedus Z 

PROVIDER: S-EPMC8179271 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature