Affinity-Driven Peptide Selection of an NFAT Inhibitor More Selective Than Cyclosporin A

• Published in: Science (American Association for the Advancement of Science) Vol. 285; no. 5436; pp. 2129 - 2133
• Main Authors: Aramburu, José, Yaffe, Michael B., López-Rodríguez, Cristina, Cantley, Lewis C., Hogan, Patrick G., Rao, Anjana
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 24.09.1999; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: Amino Acid Sequence; Amino acids; Binding Sites; Biological and medical sciences; Calcineurin - metabolism; Calcineurin Inhibitors; Calcium; Cell Nucleus - metabolism; Cellular biology; Cyclosporine - pharmacology; Cytokines; Cytokines - biosynthesis; Cytokines - genetics; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation; Genes; Genes, Reporter; HeLa Cells; Humans; Immune response; Immune response regulation; Immunobiology; Immunomodulators; Immunosuppression; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - metabolism; Immunosuppressive Agents - pharmacology; Inhibition; Jurkat Cells; Libraries; Literary Devices; Medical sciences; Mice; Modulation of the immune response (stimulation, suppression); Molecular Sequence Data; NFATC Transcription Factors; Nuclear Proteins; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacology; Peptide Library; Peptides; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Pharmacology. Drug treatments; Phosphatases; Phosphorylation; Plasmids; Recombinant Fusion Proteins - metabolism; Regulation; T cells; T lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry; Transcription Factors - metabolism; Transfection; Peptide library; Peptides; Enzyme; Immunomodulation; Phosphoprotein phosphatase; Selection; Rodentia; Phosphoric monoester hydrolases; Enzyme inhibitor; Molecular interaction; Esterases; Immunomodulator; Binding protein; Vertebrata; Mammalia; Mouse; T-Lymphocyte; Hydrolases
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.285.5436.2129

The flow of information from calcium-mobilizing receptors to nuclear factor of activated T cells (NFAT)-dependent genes is critically dependent on interaction between the phosphatase calcineurin and the transcription factor NFAT. A high-affinity calcineurin-binding peptide was selected from combinatorial peptide libraries based on the calcineurin docking motif of NFAT. This peptide potently inhibited NFAT activation and NFAT-dependent expression of endogenous cytokine genes in T cells, without affecting the expression of other cytokines that require calcineurin but not NFAT. Substitution of the optimized peptide sequence into the natural calcineurin docking site increased the calcineurin responsiveness of NFAT. Compounds that interfere selectively with the calcineurin-NFAT interaction without affecting calcineurin phosphatase activity may be useful as therapeutic agents that are less toxic than current drugs.