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Document 2 Structural Studies of HIV-1 Reverse Transcriptase and Implications for <strong>Drug</strong> <strong>Design</strong> Jianping Ding, Kalyan Das, Yu Hsiou, Wanyi Zhang, and Edward Arnold Center for Advanced Biotechnology and Medicine, and Rutgers University, Piscataway, New Jersey Prem N. S. Yadav University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey Stephen H. Hughes ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland I. Introduction Page 41 Like all other retroviruses, human immunodeficiency virus type 1 (HIV-1) contains the multifunctional enzyme reverse transcriptase (RT). Retroviral RTs have a DNA polymerase activity that can use either an RNA or a DNA template and an RNase H activity. HIV-1 RT is essential for the conversion of singlestranded viral RNA into a linear double-stranded DNA that is subsequently integrated into the host cell chromosomes [1–4]. In this conversion process HIV-1 RT catalyzes the incorporation of approximately 20,000 nucleotides. Chemotherapeutic agents have been identified that target virtually all stages of the HIV-1 replication cycle (see review [5]). Since both the polymerase and RNase H activities of HIV-1 RT are essential, inhibiting either step blocks viral replication. Therefore, HIV-1 RT is an important target for the treatment of AIDS. Two major classes of antiviral agents that inhibit HIV-1 RT polymerization have been identified; these are nucleoside RT inhibitors (NRTIs) (Figure la) and nonnucleoside RT inhibitors (NNRTIs) (Figure 1b). Nucleoside analogs, such as 3'-azido-2',3'dideoxythymidine (AZT), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxy-3'thiacyti- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_41.html [4/5/2004 4:47:13 PM]
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Page 11 and 12: Document TF—transframe, PR—prot
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Page 45 and 46: Document 47. Tummino PJ, Ferguson D
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Page 67 and 68: Document Page 54 Table 2) [12,54].
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Page 73 and 74: Document ever, once an NNRTI is bou
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Page 89 and 90: Document 30. Coffin JM. HIV populat
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Page 93 and 94: Document reverse transcriptase inhi
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Document cubation of phosphotyrosin
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Document B. Pharmacology Figure 1 T
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Document We determined the structur
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Document Figure 3 Previously known
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Document large solvent channels and
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Document IV. Drug Design Progressio
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Document position eight from formin
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Document Table 1 Inhibition Data fo
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Document Page 166 As predicated, th
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Document References 1. Parks RE Jr.
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Document 17. Ealick SE, Rule SA, Ca
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Document 6 Structural Implications
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Document Figure 1 A ribbon model of
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Document Page 176 0.43 Å) as the c
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Document Page 178 studies show that
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Document Page 182 (SAR) model. The
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Document IX. S2' Interactions Page
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Document 7 Structure—Function Rel
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Document Figure 1 Reactions catalyz
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Document Figure 2 Structure of lico
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Document Figure 3 (Continued) Page
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Document Important for the validity
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Document Figure 4 Amino acids impor
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Document III. Results and Discussio
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Document Page 202 269, and valine-2
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Document Figure 6 Structure of α h
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Document Page 205 enzyme and of phe
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Document Page 207 sure and the acti
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Document protein kinase core is ess
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Document Cyclotheonamide A (CtA), a
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Document Table 2 Naturally Occurrin
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Document Lys in the P1 position is
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Document 12 Polypeptide Modulators
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Document C. Specificity Figure 4 Th
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Document IV. Rational Drug Design F
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Document 17. Szelke M. Chemistry of
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Document Figure 8 The catalytic mac
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Document Page 359 easily reach the
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Document Table 1 Trypanosomal Targe
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Document Figure 12 Predicted bindin
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Document 16 Progress in the Design
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Document Table 1 Known Three-Dimens
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Document Page 398 with growth hormo
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Document All effects of the IL-1 fa
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Document Page 405 strands constitut
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Document Page 412 ture is unlike ot
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Document Figure 11 Functional resid
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Document Figure 13 The identified p
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Document Page 425 Antinflammatory D
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Document 5. Dinarello CA. On the Bi
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Document 39. Saurat JH, Schfferli J
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Document 17 Structure and Functiona
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document VI. Conclusion Page 480 It
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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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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