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

Nature Biotechnology volume 15, pages 1266–1270 (1997)Cite this article

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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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 252 John Morgan Building, 36th and Hamilton Walk, Philadelphia, PA, 19104-6082

    Wataru Takasaki, Yuri Kajino, Kiichi Kajino, Ramachandran Murali & Mark I. Greene

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Correspondence to Ramachandran Murali.

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Takasaki, W., Kajino, Y., Kajino, K. et al. Structure–based design and characterization of exocyclic peptidomimetics that inhibit TNFα binding to its receptor. Nat Biotechnol 15, 1266–1270 (1997). https://doi.org/10.1038/nbt1197-1266

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