We used a ligand-directed dynamic-ligation approach to identify weak binding fragments that can augment the inhibitory potency of a peptide ligand and simultaneously serve as starting points for subsequent development of PPI stabilizers using the hDMX361-371 pSer367 /14-3-3η interaction as a model. We used acylhydrazone exchange, involving acyl hydrazide peptides and readily available aldehydes together with the surface of 14-3-3η protein to template peptide-fragment hybrids. Screening of representative fragments validated the method as a conceptually distinct approach for identification of PPI stabilizers.