Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.

Normal and simian virus 40-transformed WI-38 cells exhibited a differential sensitivity to infection with type 3 reovirus. A progressive decrease in viability began 24 to 36 h after infection of transformed cells terminating in complete lysis of cultures by 96 h. Normal cells were productively infected and continued to produce and release virus for as long as 14 days after infection, but exhibited no detectable cytopathology. Inhibition of cellular DNA synthesis began 15 to 18 h after infection in transformed cells before development of cytopathology. No inhibition of DNA synthesis was detected in infected normal cells. No significant differences were noted in the adsorption or early replication characteristics of reovirus in normal and transformed cells. Virus replication and host cell DNA synthesis in normal and transformed human cells were compared to reovirusinfected L-929 mouse fibroblast cells.

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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.