Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF alpha binding to its receptor.
Exocyclic small peptidomimetics corresponding to three critical binding sites of tumor necrosis factor (TNF)-receptor(I) have been designed based on atomic features deduced from the crystal structures of TNF alpha and the TNF beta/TNF-receptor(I) complex and a model of an anti-TNF alpha monoclonal antibody. TNF alpha antagonistic activities were evaluated by binding assays using soluble receptor or intact receptor on cells as well as an apoptosis/cytotoxicity assay. The most critical interaction site for rational design of peptidomimetics was localized to the loop1/domain3 of the TNF-receptor. The best antagonist showed 5 microM inhibition in the binding assay. Biologically, the mimetics inhibited TNF alpha-mediated apoptosis.
Takasaki
W
W
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082, USA.
Kajino
Y
Y
Kajino
K
K
Murali
R
R
Greene
M I
MI
D000595:Amino Acid Sequence; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010455:Peptides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha