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A Peptidomimetic Antagonist of TNF--Mediated Cytotoxicity Identified from a Phage-Displayed Random Peptide Library¹

Carlos L. Chirinos-Rojas^*, Michael W. Steward^* and Charalambos D. Partidos^2,

^* Department of Infections and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; and Department of Pathology and Infectious Diseases, Royal Veterinary College, London, United Kingdom

Phage-displayed peptide libraries represent a vast collection of peptide sequences that can be used to identify novel therapeutic molecules. In this report, a 15-mer phage-displayed peptide library was used to identify potential TNF- antagonists. After direct interaction of recombinant human TNF- with the library, four randomly selected phage clones were shown to inhibit in a dose-dependent fashion both mouse and human TNF--induced cytotoxicity in vitro. DNA sequencing of the positive clones revealed a common amino acid sequence that does not bear any structural similarity to the known primary structures of the extracellular domains of either 55-kDa or 75-kDa TNF receptors. This sequence was synthesized, and the peptidomimotope was shown i) to bind to the recombinant human TNF- using surface plasmon resonance (biosensor) technology and ii) to inhibit both recombinant mouse and human TNF--induced cytotoxicity in vitro in a dose-dependent fashion.

These findings highlight the potential of phage-displayed random peptide libraries for the identification of novel low molecular antagonistic molecules that can block the biologic activities of TNF-.

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