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Document Figure 12 The open end of IL-1β, shown as a surface. The positions of some of the residues that have been subjected to site-directed mutagenesis studies have been marked. Produced using the program GRASP [108]. Page 418 weak agonist. Peptide 47–55 (VQGEESNDK) has been identified as an activator of T cells. It also stimulates glycosaminoglycan synthesis, excites antitumor activity in vivo, and lacks proinflammatory and pyrogenic activities [70]. Later a shorter segment (49–53 = GEESN) with higher activity than 47–55 has been identified. Peptides based on IL-1α and IL-1β sequences were claimed to induce production of prostaglandin E2 but actually maintain other biological activities. Few other peptides or peptidecontaining epitopes were identified by using neutralizing antibodies. Labriola-Tompkins and his colleagues have reported obtaining epitopes for neutralizing antibodies by fractionation of a goat polyclonal antiserum over columns containing individual immobilized synthetic http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_418.html (1 of 2) [4/5/2004 5:49:05 PM]
Document Figure 13 The identified peptide fragments. Peptide fragments are shown as striped coil, with residues at the start and end of the peptides are numbered. Produced by Molscript [106], modified by R. Esneuf. peptides derived from an IL-1α sequence [58]. Their work resulted in 4 peptide regions with residue numbers 4–12, 44–63, 64–88, and 89–105. Peptides 47–55, 81–99, 92–124, 121–153 in the 3dimensional structure of IL-1β are shown in Figure 13. E. Other Strategies Page 419 Biochemical and structural knowledge has opened many pathways for the development of novel therapeutics. Such strategies include inducer blockers, nucleotide intercalators, antisense RNAs, and other novel molecular mimics. It is known that potent inducers such as lipopolysaccharides, c5a, and integrins bind to IL-1-producing cells and induce the over expression of IL-1. Such an induction can be interrupted by raising the level of neutralizing monoclonal antibodies against the inducers. Alternatively, one can design ligands that can bind to the inducer receptors, which leads to the inhibition of the IL-1 synthesis process. Transcription factors bind to specific DNA sequences and stimulate gene transcription. Controlling such a specific gene transcription can be achieved by a number of means. Intercalators or fragments of the same DNA sequences as those bound by the transcription factors can selectively inhibit transcription. Double-stranded oligonucleotides, having the same consensus sequence, could complete with the transcription factor for binding to the promoter region. Antisense RNA, which when introduced into eukaryotic cells induces sequence-specific inhibition of target gene expression, can be used. The http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_419.html [4/5/2004 5:49:18 PM]
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Structure-based Drug Design 14 Stru
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Document 2 Structural Studies of HI
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Document Chris Tantillo. The work i
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Document dine) and didanosine (dide
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Document 163. Lacey SF, Larder BA.
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Document Page 108 mulate during tre
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Document 4 Bradykinin Receptor Anta
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Page 535 and 536: Document receptor antagonist into a
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Page 541 and 542: Document 17 Structure and Functiona
Page 543 and 544: Document Table 1 Approval Indicatio
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Page 547 and 548: Document II. Type IFNs A great deal
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Page 553 and 554: Document Figure 4 Stereo view of IF
Page 555 and 556: Document Figure 5 Velcro-key model
Page 557 and 558: Document Figure 6 Proposed receptor
Page 559 and 560: Document Page 451 with the cytoplas
Page 561 and 562: Document for directed subcellular t
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document [Protease targets] serinyl
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