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Document the virus arises because, once integrated, the viral DNA can no longer be distinguished from host cell DNA and has become a permanent fixture of the host cell genome. B. Rationale for Drug Design Against Integrase to Fight HIV and AIDS Page 85 It has been demonstrated that the chemical steps that comprise DNA integration are carried out by the viral protein, integrase (IN). Integrase is encoded by the 3' end of the viral pol gene, which also codes for two other viral enzymes, the protease and reverse transcriptase. These three enzymes are initially synthesized as part of a larger polyprotein that is subsequently cleaved by the protease to the individual proteins. Why is integrase a good target for drug-design efforts to prevent infection by halting the viral replication cycle? First, integration is required for replication. In the absence of integration, the virus is unable to continue to make copies of itself. Secondly, the enzyme that carries out integration is virally encoded, and when the viral genome is disrupted so that functional integrase is no longer made, sustained viral replication does not occur [2]. This demonstrates that if viral integrase can be effectively inhibited, there is no protein encoded by the host cell that can replace it and carry out viral integration. Finally, since mammalian cells do not have enzymes capable of integrating HIV DNA, there are no vital host cell analogs of integrase carrying out essential reactions whose function would be blocked by integrase inhibitors. Effective inhibition of HIV integrase would add to the number of sites at which the virus replication cycle can be halted. One can imagine treatment protocols in which a mixture of inhibitors, each aimed at a different viral protein, could be administered. This is known as divergent combination therapy. As structural details are a necessary starting point for rational drug design, we present here our recent results on the high-resolution three-dimensional structure of the catalytic core domain of HIV-1 integrase [3]. We also review the current literature discussing integrase inhibitors and present thoughts on ways in which knowledge of the chemical reactions carried out by integrase and its structure might direct the development of effective inhibitors. II. Biochemical Reactions Catalyzed By HIV Integrase A. In Vivo Integration Details of the initial chemical reactions that occur during HIV integration are now well understood (for reviews, see References 4,5). Once linear double-stranded DNA is available for integration, (Figure 2a) integrase then removes http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_85.html [4/5/2004 4:54:29 PM]
Document Figure 2 In vivo reactions carried out by HIV integrase. Page 86 two nucleotides from each 3' end of the viral DNA (Figure 2b). The two nucleotides are removed as a dinucleotide rather than in two individual steps. The specificity for this reaction is conferred by the third and fourth nucleotides from each 3' end, a -CA sequence that is absolutely conserved. Once two nucleotides have been removed, leaving recessed 3' hydroxyl groups, the next step is the joining of the 3' ends to target DNA (Figure 2c, d). This process, known as double-ended integration, occurs on opposite strands such that the joining sites on each of the target DNA strands are separated by five base pairs. The final step in integration is the repair of the single-stranded gaps generated by the staggered insertion of the viral 3' ends on opposite strands; this regenerates an intact double-stranded DNA molecule (Figure 2e and f). Gap repair is probably carried out by host cell DNA repair systems. One necessary consequence of retroviral integration is the duplication of five base pairs of host cell DNA on either side of the integrated provirus. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_86.html [4/5/2004 4:54:34 PM]
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Page 67 and 68: Document Page 54 Table 2) [12,54].
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Page 81 and 82: Document Page 67 Biochemical data s
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Page 85 and 86: Document Chris Tantillo. The work i
Page 87 and 88: Document Page 72 16. Goldman ME, Nu
Page 89 and 90: Document 30. Coffin JM. HIV populat
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Page 103 and 104: Document dine) and didanosine (dide
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Page 117 and 118: Document Page 92 The role of the N-
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Page 149 and 150: Document 4 Bradykinin Receptor Anta
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