The design and synthesis of two pyrrolinone-peptide hybrid ligands (3 and 20) for the rheumatoid arthritis-associated class II MHC HLA-DR1 protein are described. The hybrids incorporate bispyrrolinones 4 and 21 as tetrapeptide mimics for amino acids VKQN (residues 309-312) of the virus hemagglutinin peptide HA 306-318 (PKYVKQNTLKLAT). Ligand construction employed our polypyrrolinone synthetic protocol, in conjunction with Fmoc-based solid-phase peptide synthesis. Bioaffinity studies reveal that hybrid ligand 3 bound the HLA-DR1 protein with affinity (IC50 = 137 nM) comparable to those of both the native HA 306-318 peptide (IC50 = 89 nM) and a control peptide (IC50 = 176 nM). This result demonstrates that the polypyrrolinone scaffold can be employed in the construction of bioactive peptide hybrid ligands, thus considerably expanding the scope and utility of the pyrrolinone scaffold.