Structure–based design and characterization of exocyclic peptidomimetics that inhibit TNFα binding to its receptor

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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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Correspondence to Ramachandran Murali.

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