Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNF alpha binding to its receptor

Nat Biotechnol. 1997 Nov;15(12):1266-70. doi: 10.1038/nbt1197-1266.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Mimicry*
  • Peptides / chemistry*
  • Peptides / pharmacology
  • Protein Binding
  • Protein Conformation
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism


  • Peptides
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha