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Document VI. Conclusion Page 428 The design of novel compounds to inhibit or manipulate the IL-1 system remains a daunting task. At this time, the design of immunomodulators for the IL-1 system is still in its infancy and has largely been confined to the use of whole or fragmented proteins or the identification of nonspecific small molecules. In addition, newer approaches have also been initiated and these include the use of antisense oligonucleotides, small molecules designed to compete with IL-1's binding to its receptor, ICE inhibitors, and intracellular signaling inhibitors. All such strategies show promise. Structure-based design has not been explicitly used in the design of agonists and antagonists of IL-1. But as of now we have the structures of IL-1α, IL-1β, and IL-1Ra. A new insight may be forthcoming once the complex crystallographic structure of one of the interleukin-1 molecules and its corresponding receptor molecule is available. This structural information, coupled with the anticipated IL-1 + IL-1R complex structure, will form the foundation for rational design of inhibitors with improved selectivity for the treatment of various IL-1-mediated diseases. Acknowledgements Our special thanks to Professor Russell Doolittle for his encouragement and support, and also to Dr. Mitch Lewis for providing us with the very high-resolution coordinates of IL-1α. We gratefully acknowledge San Diego Super Computing Center for their assistance and support in providing valuable software and high-power computing time. We thank Dr. Donald Kyle for his valuable comments. We also thank Dr. Per Kraulis for providing us the latest version of MOLSCRIPT, Dr. Anthony Nicholls for the program GRASP, Dr. Rob Russell for the structural alignment, and Professor Lynn Ten Eyck and Dr. Jerry Greenberg for their help. References 1. Dinarello CA. Biological basis for interleukin-1 in disease. Blood 1996; 87- 6:2095–2147. 2. Dinarello CA. Interleukin-1 is produced in response to infection and injury. Rev infect Dis 1984;6:51–56. 3. Oppenheim JJ, Kovacs EJ, Matsushima K, Durum SK. There is more than one interleukin 1. Immunol Today 1986;7:45–56. 4. Durum KS, Oppenheim JJ, Neta R. Immunophysiologic role of interleukin-1. In: Oppenheim JJ, Shevach EM, eds. Immunophysiology. New York: Oxford University Press, 1990:210–225. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_428.html [4/9/2004 12:10:04 AM]
Document 5. Dinarello CA. On the Biology of Interleukin-1. Adv Immunology 1989; 44:153– 205. Page 429 6. Meager A. Cytokines. 1990; Open University Press. 7. Henderson B, Blake S. Therapeutic Advantage of Cytokine Manipulation. TIPS 1992; 13:145–152. 8. Dower SK, Fanslow W, Jacobs C, Waugh S, Sims JE, Widmer MB. Interleukin-1 antagonists. Therapeutic Immunol 1994; 1:113. 9. Burger DD, J. Inhibitory Cytokines and Cytokine Inhibitors. Neurology 1995; 45(supp 16):s39–43. 10. Abraham DJ. X-ray crystallography and drug design. In: Perun TJ, Propst CL, eds. Computer Aided Drug Design. New York: Marcel Dekker, Inc., 1989:93–132. 11. Fesik SW. Approaches to drug design using nuclear magnetic resonance spectroscopy. In: Perun TJ, Propst CL, eds. Computer-Aided Drug Design. New York: Marcel Dekker, Inc., 1989:133–184. 12. Veerapandian B. Structure aided drug design. In: Wolf M, ed. Buerger's Drug Discovery and Medicinal Chemistry. New York: John Wiley and Sons, 1995:303– 348. 13. Whittle PJ, Blundell TL. Protein Structure based drug design. Ann Rev Biophy and Biomol Structure 1994; 23:349–375. 14. Carter DB, Deibel MRJ, Dunn CJ, Tomich C-SC, Laborde AL, Slightom JL. Berger AE, Bienkowski MJ, Sun FF, McEwan RN, Hams PKW, Yem AW, Waszak GA, Chosay JG, Sieu LC, Hardee MM, Zucher-Neely HA, Reardon IM, Heinnckson RL, Truesdell SE, Shelly JA, Eessalu TE, Taylor BM, Tracey DE. Purification, cloning, expression, and biological characterization of an interleukin-1 receptor antagonist protein. Nature 1990; 344:633–638. 15. Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature, 1990; 343:341–346. 16. Sims JE, March CJ, Cosman D, Widmer MB, MacDonald HR, McMahan CJ, Grubin CE, Wignall JM, Jackson JL, Call SM, et al. cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science 1988; 241:585. 17. McMahon CJ, Slack JL, Mosley B, Cosman D, Lupton SD, Brunton LL, Grubin CE, Wignall JM, Jenkins NA, Brannan C1, Copeland NG, Huebner K, Croce CM, Cannizzaro LA, Benjamin D, Dower S, Spriggs MK, Sims JE. A novel IL-1 receptor cloned from B cells by mammalian expression is expressed in many cell types. EMBO J 1991; 10:2821. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_429.html (1 of 2) [4/9/2004 12:10:07 AM]
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Document [Human immunodeficiency vi
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Document overview, 103-104, 108-109
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Document [Inhibitors] 2-((3,4-dihyd
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Document antagonistic activity, 416
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Document [Interleukin-1] homology w
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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