Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF alpha binding to its receptor.
basic_science · Level V
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Abstract
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.
Medical subject headings
- Molecular Mimicry
- Peptides
- Receptors, Tumor Necrosis Factor
- Tumor Necrosis Factor-alpha