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Document Page 28 aspartic acid residues Asp25/25' and this hydrogen-bonding network of the 4-hydroxycoumarin defines the essential pharmacophore of this new class of inhibitors. In the structure of U96988, this pharmacophore is pseudosymmetrically subsituted by an ethyl and a phenyl group at the C-3a and an ethyl and a benzyl group at the C-6a positions. These four substituents extend into the central core of S2/S2' subsites, where they make van der Waals contacts with the hydrophobic residues of the active site [49]. With a molecular weight of 362 U96988 is the smallest inhibitor of HIV PR in clinical testing. It suffers from rather low antiviral activity (ED90 of ~ 10 μM)but can be considered as the first in a series of this promising class of nonpeptidic HIV PR inhibitors. II. Structural Basis of Resistance of HIV PR Inhibitors The dimeric character and the two-fold symmetry of the active site, in which the monomers contribute equivalent residues to symmetrically distributed specificity subsites, led to early speculations that HIV PR may be less susceptible to resistance than, for example, reverse transcriptase. In the case of retroviral proteases, a single base mutation in the viral genome corresponds to two changes in the threedimensional structure and two structurally identical changes in the active site could result in an enzyme with a drastically modified specificity profile and impaired catalytic activity. Identification of HIV PR variants in cell-culture experiments clearly indicated, however, that this class of drugs is not immune to the challenge of viral resistance. It should be stressed that HIV, unlike other human viruses, is characterized by a dynamic viral turnover in the steady state [51,52]. The rapid replication rate coupled with the lengthy duration of infection will favor the emergence of resistant mutants to targeted antiviral agents [53]. The accumulated data from cell-culture sequential-passage experiments with several structurally different inhibitors and from the resistant variants identified during clinical exposure to four HIV PRtargeting drugs indicate a very complex pattern of mutations in the structure of HIV PR. In contrast to mutations in the reverse transcriptase, which frequently cause multihundredfold resistance [54], single base changes in the HIV PR gene (i.e., two identical substitutions per protease dimer) lead in most cases to 5–10-fold decrease in the antiviral potency of a given drug [11]. It has been shown for the most clinically studied HIV PR inhibitors, such as indinavir and ritonavir, that the clinical manifestation of resistance (increase in the viral load and decrease in the CD4 count) requires the simultaneous appearance of several mutations [55,56]. For example the resistant HIV strain isolated from patients exposed for 40 weeks to indinavir carried mutations at residues 10/10'L > R, 46/46'M > I, 63/63'L > P, 82/82'V > T, and 84/84'I > V [59,60]. However, the combination of these five http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_28.html [4/5/2004 4:46:29 PM]
Document Figure 7 Cartoon representation of the HIV PR dimer. The sites of primary resistance-causing mutations in the active site are indicated. For clarity, the names of the residues are shown for one monomer only. Page 29 mutations (ten assuming the dimeric nature of HIV PR) changed the susceptibility of the resistant strain to indinavir by only eight-fold if compared to the wild type HIV. The resistance-causing mutations are localized in a few “hot spots” in the structure of HIV PR and can be divided into two groups. The first group consists of the primary mutations located directly in the active site and includes changes at residues Val82/82', Ile84/84', somewhat less frequently at Gly48/48' and, in the case of nelfinavir, Asp30/30' (Figure 7). Residues 82/82' and 84/84' are located on the flexible loops that form the outer walls of the S3/S3' and S1/S1' subsites, respectively. In the resistant variants, valine 82/82' is most frequently substituted by the smaller side chain of alanine or the larger side chains of phenylalanine or isoleucine [57,58]. The change in position 82/82' is usually accompanied by a substitution of Ile84/84', most commonly to the smaller amino acids alanine or valine [57]. From the clinically tested compounds, ritonavir and indinavir, which were optimized to form strong hydrophobic interactions with the side chain of Val82/82' in the S3 subsite, suffer most significantly from any change at this position. On the other hand, the antiviral activities of saquinavir, and nelfinavir, which do not form any interaction in the S3/S3' subsite are not affected by mutations at Val82/82' and are only marginally cross resistant to changes involving Ile84/84' [57,58,62]. The resistance-causing http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_29.html [4/5/2004 4:46:39 PM]
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Page 11 and 12: Document TF—transframe, PR—prot
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Page 37 and 38: Document Page 33 sustained in many
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Page 45 and 46: Document 47. Tummino PJ, Ferguson D
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Page 51 and 52: Document 2 Structural Studies of HI
Page 53 and 54: Document Figure 1 (a) Chemical stru
Page 55 and 56: Document dine (3TC), and 2',3'-dide
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Page 63 and 64: Document monophosphate analogs whic
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Page 67 and 68: Document Page 54 Table 2) [12,54].
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Document Page 69 determining the me
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Document Chris Tantillo. The work i
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Document Page 72 16. Goldman ME, Nu
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Document 30. Coffin JM. HIV populat
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Document 45. Majumadar C, Abbotts J
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Document reverse transcriptase inhi
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Document 106. Cirino NM, Cameron CE
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Document dine) and didanosine (dide
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Document 149. Craig JC, Duncan IB,
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Document 163. Lacey SF, Larder BA.
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Document Figure 1 Retroviral lifecy
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Document Figure 2 In vivo reactions
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Document Page 88 transfer (Figure 3
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Document Page 92 The role of the N-
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Document Figure 6 Molscript stereo
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Document Page 96 region in the HIV-
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Document day junction resolving enz
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Document -62° for HIV-1 integrase,
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Document Page 101 crystallized unde
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Document Figure 8 Molscript stereo
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Document proposed mechanisms. For e
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Document Page 106 on the same ring
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Document Page 108 mulate during tre
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Document when metals are bound. Fin
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Document cubation of phosphotyrosin
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Document 65. Gallay P, Swingler S,
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Document 4 Bradykinin Receptor Anta
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Document Page 121 Nearly all cells
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Document Page 125 binding site on t
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Document receptor, it has not yet b
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Document Page 135 might be jointly
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Document Page 137 observed for the
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Document Figure 6 Rat and human B2
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Document Page 141 receptor with int
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Document Figure 9 Composition of te
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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 Figure 6 (a) The pocket of
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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 29. Baker ME. Genealogy of
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Document protein kinase core is ess
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Document 9 Structural Studies of Al
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Document diverse ARIs have been sho
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Document Figure 4 Surface represent
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Document Figure 7 Stereo of zopolre
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Document B. Structures Figure 8 Seq
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Document This method was used to sc
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Document Cyclotheonamide A (CtA), a
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Document Page 256 The discovery pro
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Document balance its pro- and antic
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Document Page 263 15. Tabernero L,
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Document 31. Kettner C, Shaw E. D-P
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Document Figure 1 The coagulation c
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Document Figure 2 Factor Xa structu
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Document Table 2 Naturally Occurrin
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Document Table 3 Active Site Sequen
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Document Figure 5 Predicted seconda
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Document Lys in the P1 position is
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Document Page 276 In both cases the
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Document Page 278 The n=3 chain len
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Document Figure 10 Proposed model o
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Document Figure 11 dArg-ATS 32-38 m
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Document Figure 12 Modeled fit of S
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Document Page 285 number of x-ray s
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Document 12 Polypeptide Modulators
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Document Page 297 whereas, calcium
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Document Figure 2 Amino acid sequen
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Document A. Chemical Modification P
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Document Page 314 anemone toxins an
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Document 13 Rational Design of Reni
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Document Page 323 been suggested th
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Document plasma. This may arise fro
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Document C. Specificity Figure 4 Th
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Document Figure 5 The S 3 specifici
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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 Figure 1 Available drugs f
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Document Table 1 Trypanosomal Targe
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Document Table 2 Three-Dimensional
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Document 5-Methoxytryptamine 19.0 9
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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 Figure 4 (a) Stereo diagra
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Document Figure 7 (a) Superposition
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Document Page 412 ture is unlike ot
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Document Page 416 positions of the
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Document Figure 11 Functional resid
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Document Figure 13 The identified p
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Document B. Interleukin-1 Receptor
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Document Page 423 American Home Pro
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Document Page 425 Antinflammatory D
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Document Page 427 These aromatic di
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Document 5. Dinarello CA. On the Bi
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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 II. Type IFNs A great deal
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Document Page 443 that allowed for
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Document Figure 4 Stereo view of IF
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Document Figure 5 Velcro-key model
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Document hydroxy, and 6 Neu5Ac2en -
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Document RT inhibitor, 41, 56 Nonpe
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