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Document Page 452 ligand and the machinery of signal transduction, namely JAK2. It was found that both intact murine IFNγ and its C-terminal peptide (95–133) are capable of specifically mediating an increase in the degree of association between the recombinant, soluble IFN-γ receptor and JAK2. These findings were further supported as IFN-γ and IFN-γ (95–133) caused an increase in the amount of JAK2 coprecipitating with the receptor from intact murine macrophages [58]. This has been the first such demonstration of an extracellular cytokine ligand participating directly in interaction with cytoplasmic signaling elements. E. IFN-γ as a Candidate for Rational Drug Design The IFN-γ molecule is a potentially attractive model for the rational application of drug-design strategies. Reagents exist that are capable of either positively or negatively modulating the in vivo effects of IFN-γ. An initial target is quite simply at the level of receptor-ligand interaction. Synthetic peptide analogs of the N-terminal region have been successfully applied in vitro to inhibit interaction of intact IFN-γ with cell-surface receptors [30]. Interestingly, it has been observed that the N-terminal region of mouse IFN-γ has the ability to interact with the human receptor [59]. It was shown that the mouse peptide IFN-γ (1–39) had a 10-fold greater ability to block the binding of human IFN-γ to cellsurface receptors. This was shown to be correlated with a more stable structure in solution for the murine peptide and illustrates the importance of stable structure to receptor binding, which may be exploited when designing peptide mimetics. The solution structure of this peptide has also been determined and could provide the beginning steps for determining the structural requirements of an antagonist [7]. Future studies could focus on cocrystallization of the peptides with receptor or NMR studies of peptide domains of the receptor and IFN-γ. Recombinant, soluble forms of the extracellular domain of the ligand-binding subunit of the receptor have also been used in analogous fashion both in vitro to inhibit cell-surface binding and in vivo to interfere with disease progression [60]. Therefore prevention of potentially deleterious effects of IFN-γ may be achieved by preventing initial interactions with receptor molecules at the cell surface. A second candidate region lies within amino acid residues 84–94 of human IFN-γ and the corresponding region of its murine homologue. This portion of the molecule functions as a nuclear localization signal and, therefore, is also an attractive target for drug design. In cells treated with IFN-γ, the IFN-γ molecule traffics rapidly to the nucleus of the cell, usually within one to two minutes. When the IFN-γ molecule is crosslinked to its receptor, the resultant receptor-ligand complex migrates to the nucleus [40]. The implication is that this sequence may therefore be of use in artificially targeting proteins from the cytoplasm directly to the nucleus. This is potentially a very attractive method http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_452.html [4/9/2004 12:12:03 AM]
Document for directed subcellular targeting of synthetic transcriptional activators or repressors that might not otherwise be directed to the nucleus. Page 453 Finally, the C-terminal region of IFN-γ offers another possibility. With respect to the induction of an antiviral state, or the upregulation of MHC class II molecule expression, synthetic peptides corresponding to the C-terminal 39 amino acids of either human or murine IFN-γ function as potent agonists. This activity is due to the interaction of these peptides with the cytoplasmic domain of the IFNγ receptor and the associated protein tyrosine kinases. Furthermore, in contrast to the stringent species specificity of intact IFN-γ, the action of the C-terminal peptides agonists is not limited by species constraints. This property therefore renders the C-terminal portion of the IFN-γ molecule an attractive model for the development of IFN-γ agonists and antagonists. The identification of the C-terminus of IFN-γ as that part of the molecule that contacts the cytoplasmic portion of the receptor implies that in developing IFN-γ agonists, the primary focus should be on this region of the protein. Corresponding antagonists may be developed based upon the portion of the receptor to which the IFN-γ C-terminus binds. IV. Conclusion The interest in IFNs as therapeutics has existed from their initial discovery in 1957. Since then scientists have been trying to understand the mechanism of their action and apply that knowledge to the treatment of many different diseases, meeting with some success. The effort now is to understand how IFNs work at the molecular level, with the goal being to design better, more specific therapeutics. Through structure/function studies, we now know where the functional sites lie on many of the IFNs. We also know the sites of interaction with their receptors and second messenger systems. From these studies, initial candidates for structure-based drug design have been identified. Although more work is needed to further characterize the IFNs and their receptor systems, the challenge now is to apply our existing knowledge and create second generation molecules that can modulate the many activities of these fascinating proteins. References 1a. Isaacs A and Lindenmann J. Virus Interference. I. The interferon. Proc R Soc London Ser B 1957; 147:258. 1b. Johnson HM, Bazer FW, Szente BE, Jarpe MA. How interferons fight disease. Scientific American 1994; 270:40–47. 2. Senda T, Shimazu T, Matsuda S, Kawano G, Shimizu H, Nakamura KT, Mitsui Y. Three-dimensional crystal structure of recombinant murine interferon-β. EMBO J 1992; 11:3193–3201. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_453.html (1 of 2) [4/9/2004 12:12:07 AM]
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