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Document Figure 1 Interferon activity. Page 436 receptor activation are similar. These pathways involve ligand and receptor binding followed by the activation of tyrosine kinases and the phosphorylation of various proteins and their subsequent interaction with transcription elements on DNA. The two receptor activation pathways differ at the level of ligand binding. Type I IFNs bind their receptor as a complex of a single ligand, ligand binding element, and an accessory molecule. The Type II binding event occurs as a dimer of IFN-γ binding to two identical receptor molecules leading to receptor dimerization and activation. The IFNs of all subclasses posses antiviral activity. Additionally, they produce cellular responses that are distinct from antiviral activity, including antiproliferative and immunomodulatory activities (Figure 1). These activities have led to an interest in their use as potential therapeutics to combat viral disease, cancer, and autoimmune disease. Currently, the IFNs have a worldwide market in excess of 2 billion dollars annually. There are six FDA-approved indications in the United States with several more in clinical trials (Table 1). In fact, two of the top-ten grossing biotechnology-based drugs on the U.S. market are IFNs. Intron A is an IFN-α used for immune protection and has an annual U.S. market of $570 million. Roferon-A is another IFN-α used for hairy-cell leukemia and Kaposi's sarcoma with an annual market of $170 million. These sales are despite profound negative side effects associated with IFN treatment. High doses are required to achieve positive clinical results and can lead to severe flu-like symptoms including nausea, vomiting, and fever. These side effects can cause patients to drop out of treatment before beneficial effects are seen. Another drawback of IFNs as drugs is that they require parenteral delivery. The IFNs are protein drugs that must be administered by injection and http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_436.html [4/9/2004 12:10:34 AM]
Document Table 1 Approval Indications for IFNs FDA Approved Clinical Trials IFN-α Chronic hepatitis HIV infection Kaposi's sarcoma Colon tumors Genital warts (papillomavirus) Kidney tumors Bladder cancer Hairy cell leukemia Malignant melanoma Non-Hodgkin's lymphoma Chronic myelogenous leukemia Throat wartz (papillomavirus) IFN-β Relapsing remitting multiple sclerosis Basal cell carcinoma IFN-γ Chronic granulomatous disease Kidney tumors Leishmaniasis cannot be given orally. For many of the clinical indications, treatments of many months are needed requiring repeat injections. Page 437 These drawbacks, coupled with the market value of IFN-related treatments, now and in the future, have created an interest in producing second-generation molecules that can mimic IFN activity. These “mimetics” could potentially have greater specificity with fewer side effects. They may also have the advantages of reduced manufacturing costs and more versatile delivery. The design of mimetics can be achieved through structure-based drug design methodologies that are currently being developed. However, in order to apply structure-based drug design to a protein, a solid understanding of the structure/function relationship is needed. A three-dimensional structure, taken alone, gives little insight into the activity of a protein. Structure/function studies must be done for the full potential of structurebased drug design to be realized. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_437.html (1 of 2) [4/9/2004 12:10:37 AM]
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