Structure–based design and characterization of exocyclic peptidomimetics that inhibit TNFα binding to its receptor
W Takasaki, Y Kajino, K Kajino, R Murali… - Nature …, 1997 - nature.com
Exocyclic small peptidomimetics corresponding to three critical binding sites of tumor
necrosis factor (TNF)-receptor (l) have been designed based on atomic features deduced
from the crystal structures of TNFα and the TNFβ/TNF-receptor (l) complex and a model of an
anti-TNFα monoclonal antibody. TNFα 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 …
necrosis factor (TNF)-receptor (l) have been designed based on atomic features deduced
from the crystal structures of TNFα and the TNFβ/TNF-receptor (l) complex and a model of an
anti-TNFα monoclonal antibody. TNFα 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 …
Abstract
Exocyclic small peptidomimetics corresponding to three critical binding sites of tumor necrosis factor (TNF)-receptor(l) have been designed based on atomic features deduced from the crystal structures of TNFα and the TNFβ/TNF-receptor(l) complex and a model of an anti-TNFα monoclonal antibody. TNFα 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 Ioop1/domain3 of the TNF-receptor. The best antagonist showed 5 μM inhibition in the binding assay. Biologically, the mimetics inhibited TNFα-mediated apoptosis.
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