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Structural Studies on HIV Reverse Transcriptase Related to Drug Discovery

  • David K. Stammers
  • Jingshan Ren
Part of the Infectious Disease book series (ID)

Abstract

The problems to human health posed by the AIDS epidemic have prompted wide-ranging research into the causative agent, HIV (1 . A greater knowledge of the virus, including a detailed understanding of the structure and function of HIV-encoded gene products is generally expected to be valuable in designing new therapies. HIV, a retroviridae family member, has a relatively small, single-stranded positive sense ribonucleic acid (RNA) genome that contains three main genes (gag, pol, and env) as well as regulatory (tat and rev) and accessory (vif, nef, vpr, and vpu) genes. Although certain of the gene products (such as gag-pol) are further processed to smaller proteins, there is a relatively limited number of potential virus-specific targets against which to develop drugs. The virus-encoded deoxyribonucleic acid (DNA) polymerase has been a cornerstone target for anti-HIV drug discovery because it produces copies of the viral genome, a key step in the replication of HIV. Retrovirus polymerases are referred to as reverse transcriptases (RTs) because the flow of genetic informati on is from RNA to DNA, the opposite direction to that normally specified. Because of its important role as the target for many anti-AIDS drugs, HIV RT (almost exclusively from the HIV-1 serotype) has been the subject of extensive structural biology studies, particularly studies using X-ray crystallography (2, 3, 4, 5). Such studies have been performed with a number of objectives in mind, but, in the context of drug discovery, the key areas of interest include understan ding the binding properties of inhibitors, investigating the mechanisms of drug resistance at the molecular level, and structure-based drug design.

Keywords

Mutant Reverse Transcr Stal Structure Reverse Transcr Heterodimer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retro-virus from a patient at risk for acquired immunodeficiency syndrome (AIDS). Science 1983;220:868–871.PubMedCrossRefGoogle Scholar
  2. 2.
    Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 1992;256:1783–1790.PubMedCrossRefGoogle Scholar
  3. 3.
    Jacobo-Molina A, Ding JP, Nanni RG, et al. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA. Proc Natl Acad Sci USA 1993;90: 6320–6324.PubMedCrossRefGoogle Scholar
  4. 4.
    Ren J, Esnouf R, Garman E, et al. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nat Struct Biol. 1995;2:293–302.PubMedCrossRefGoogle Scholar
  5. 5.
    Rodgers DW, Gamblin SJ, Harris BA, et al. The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1995;92:1222–1226.PubMedCrossRefGoogle Scholar
  6. 6.
    Goff SP. Retroviral reverse transcriptase: synthesis, structure, and function. J Acquired Immune Defic Syndr 1990;3:817–831.Google Scholar
  7. 7.
    Barat C, Schatz o, Le Grice S, Darlix JL. Analysis of the interactions of HIV1 replication primer tRNA (Lys,3) with nucleocapsid protein and reverse transcriptase. J Mol Biol. 1993;231(2):185–190.PubMedCrossRefGoogle Scholar
  8. 8.
    Lowe DM, Aitken A, Bradley C, et al. HIV-1 reverse transcriptase: crystallisation and analysis of domain structure by limited proteolysis. Biochemistry 1988;27: 8884–8889.PubMedCrossRefGoogle Scholar
  9. 9.
    Di Marzo Veronese F, Copeland TD, De Vico AL, et al. Characterization of highly immunogenic p66/p51 as the reverse transcriptase of HTLV-III/LAV. Science 1986;231:1289–1291.PubMedCrossRefGoogle Scholar
  10. 10.
    Mishima Y Steitz JA. Site-specific crosslinking of 4-thiouridine-modified human tRNA 3Lys to reverse transcriptase from human immudeficiency virus type I. Embo J 1995;14112679–2687Google Scholar
  11. 11.
    Fyfe JA, Keller PM, Furman PA, Miller RL, Elion GB. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxy-ethoxymethyl)guanine. J Biol Chem. 1978;253(24):8721–8727.PubMedGoogle Scholar
  12. 12.
    Furman PA, Fyfe JA, St Clair MH, et al. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci USA 1986;83:8333–8337.PubMedCrossRefGoogle Scholar
  13. 13.
    Goody RS, Muller B, Restle T. Factors contributing to the inhibition of HIV reverse transcriptase by chain-terminating nucleotides in vivo. FEBS Lett 1991;291:1–5.PubMedCrossRefGoogle Scholar
  14. 14.
    LeLacheur SF, Simon GL. Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine. J Acquir Immune Defic Syndr 1991;4(5):538–539.PubMedGoogle Scholar
  15. 15.
    Baba M, Tanaka H, De Clercq E, et al. Highly specific inhibition of human immunodeficiency virus type-1 by a novel 6-substituted acyclouridine derivative. Biochem Biophys Res Commun. 1989;165:1375–1381.PubMedCrossRefGoogle Scholar
  16. 16.
    Merluzzi VJ, Hargrave KD, Labadia M, et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 1990;250:1411–1413.PubMedCrossRefGoogle Scholar
  17. 17.
    Ren J, Diprose J, Warren J, et al. Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases: structural and biochem-ical analyses. J Biol Chem. 2000;275:5633–5639.PubMedCrossRefGoogle Scholar
  18. 18.
    Schinazi RF, Larder BA, Mellors JW. Mutations in retroviral genes associated with drug resistance. International Antiviral News 2000;8:65–71.Google Scholar
  19. 19.
    Young SD, Britcher SF, Tran Lo, et al. L-743, 726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother 1995;39:2602–2605.PubMedGoogle Scholar
  20. 20.
    Fujiwara T, Sato A, el-Farrash M, et al. S-l 153 inhibits replication of known drug-resistant strains of human immunodeficiency virus type 1. Antimicrob Agents Chemother 1998;42:1340–1345.PubMedGoogle Scholar
  21. 21.
    Coffin J. HIV Population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995;267:483–489.PubMedCrossRefGoogle Scholar
  22. 22.
    Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989;243:1731–1734.PubMedCrossRefGoogle Scholar
  23. 23.
    Larder BA, Kemp SD. Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 1989;246:1155–1158.PubMedCrossRefGoogle Scholar
  24. 24.
    Richman DD, Havlir D, Corbeil J, et al. Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol 1994;68:1660–1666.PubMedGoogle Scholar
  25. 25.
    Davies II, JF, Hostomska Z, Hostomsky Z, Jordan SR, Matthews DA. Crystal structure of the Ribonuclease H domain of HIV-1 reverse transcriptase. Science 1991;252:88–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Unge T, Knight S, Bhikhabhai R, et al. 2.2 Å resolution structure of the amino-terminal half of HIV-1 reverse transcriptase (fingers and palm subdomains). Structure 1994;2:953–961.PubMedCrossRefGoogle Scholar
  27. 27.
    Georgiadis MM, Jessen SM, ogata CM, Telesnitsky A, Goff SP, Hendrickson WA. Mechanistic implications from the structure of a catalytic fragment of Moloney murine leukemia virus reverse transcriptase. Structure 1995;3:879–892.PubMedCrossRefGoogle Scholar
  28. 28.
    Sarafianos SG, Das K, Tantillo C, et al. Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. Embo J 2001;20(6):1449–1461.PubMedCrossRefGoogle Scholar
  29. 29.
    Huang H, Chopra R, Verdine GL, Harrison SC. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 1998;282:1669–1675.PubMedCrossRefGoogle Scholar
  30. 30.
    Jaeger J, Restle T, Steitz TA. The structure of HIV-1 reverse transcriptase com-plexed with an RNA pseudoknot inhibitor. Embo J 1998;17(15):4535–4542.PubMedCrossRefGoogle Scholar
  31. 31.
    Esnouf R, Ren J, Ross C, Jones Y, Stammers D, Stuart D. Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat Struct Biol. 1995;2:303–308.PubMedCrossRefGoogle Scholar
  32. 32.
    Hsiou Y, Ding J,, Das K,, Clark AD Jr, Hughes SH, Arnold E. Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms. Structure 1996;4(7):853–860.PubMedCrossRefGoogle Scholar
  33. 33.
    Hogberg M, Sahlberg C, Engelhardt P, et al. Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogues. J Med Chem. 1999;42(20):4150–4160.PubMedCrossRefGoogle Scholar
  34. 34.
    Stammers DK, Somers DoN, Ross CK, et al. Crystals of HIV-1 reverse transcriptase diffracting to 2.2 Å resolution. J Mol Biol. 1994;242:586–568.PubMedCrossRefGoogle Scholar
  35. 35.
    Esnouf RM, Ren J, Garman EF, et al. Continuous and discontinuous changes in the unit cell of HIV-1 reverse transcriptase crystals on dehydration. Acta Crystallogr 1998;D54:938–954.Google Scholar
  36. 36.
    Ren J, Esnouf R, Hopkins A, et al. The structure of HIV-1 reverse transcriptase com-plexed with 9-chloro-TIBo: lessons for inhibitor design. Structure 1995;3:915–926.PubMedCrossRefGoogle Scholar
  37. 37.
    Ding J Das K Hsiou Y, et al. Structure and functional implications of the poly merase active-site region in a complex of HIV-1 RT with a double-stranded DNA template-primer and an antibody Fab fragment at 2.8 A resolution. J Mol Biol. 1998;284(4):1095–1111.PubMedCrossRefGoogle Scholar
  38. 38.
    Boyer PL, Tantillo C, Jacobo-Molina A, et al. Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug-resistant mutants does not. Proc Natl Acad Sci USA 1994;91:4882–4886.PubMedCrossRefGoogle Scholar
  39. 39.
    Sarafianos SG, Das K, Clark AD Jr, et al. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci USA 1999;96:10,027–10,032.PubMedCrossRefGoogle Scholar
  40. 40.
    Ren J, Esnouf RM, Hopkins AL, et al. 3′-azido-3′-deoxythymidine drug resistance mutations in HIV-1 reverse transcriptase can induce long range conformational changes. Proc Natl Acad Sci USA 1998;95:9518–9523.PubMedCrossRefGoogle Scholar
  41. 41.
    Schinazi RF, Lloyd RM Jr, Nguyen MH, et al. Characterization of human immuno deficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother 1993;37:875–881.PubMedGoogle Scholar
  42. 42.
    Tisdale M, Kemp SD, Parry NR, Larder BA. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3′-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci USA 1993;90:5653–5656.PubMedCrossRefGoogle Scholar
  43. 43.
    Sluis-Cremer N, Arion D, Parniak MA. Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Cell Mol Life Sci. 2000;57:1408–1422.PubMedCrossRefGoogle Scholar
  44. 44.
    Canard B, Sarfati SR, Richardson CC. Enhanced binding of azidothymidine-resistant human immunodeficiency virus 1 reverse transcriptase to the 3′-azido-3′-deoxythymidine 5′-monophosphate-terminated primer. J Biol Chem. 1998;273(23): 14,596–14,604.PubMedCrossRefGoogle Scholar
  45. 45.
    Arion D, Kaushik N, McCormick S, Borkow G, Parniak MA. Phenotypic mecha-nism of HIV-1 resistance to 3′-azido-3′-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. Biochemistry 1998;37:15,908–15,917.PubMedCrossRefGoogle Scholar
  46. 46.
    Meyer PR, Matsuura SE, Mian AM, So AG, Scott WA. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell. 1999;4:35–43.PubMedCrossRefGoogle Scholar
  47. 47.
    Meyer PR, Matsuura SE, Schinazi RF, So AG, Scott WA. Differential removal of thymidine nucleotide analogues from blocked DNA chains by human immunodeficiency virus reverse transcriptase in the presence of physiological concentrations of 2′-deoxynucleoside triphosphates. Antimicrob Agents Chemother 2000;44(12): 3465–3472.PubMedCrossRefGoogle Scholar
  48. 48.
    Lennerstrand J, Hertogs K, Stammers DK, Larder BA. Correlation between viral resistance to zidovudine and resistance at the reverse transcriptase level for a panel of human immunodeficiency virus type 1 mutants. J Virol 2001;75:7202–7205.PubMedCrossRefGoogle Scholar
  49. 49.
    Boyer PL, Sarafianos SG, Arnold E, Hughes SH. Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision. J Virol 2002;76(18): 9143–9151.PubMedCrossRefGoogle Scholar
  50. 50.
    Lennerstrand J, Stammers DK, Larder BA. Biochemical mechanism of human immunodeficiency virus type 1 reverse transcriptase resistance to stavudine. Antimicrob Agents Chemother 2001;45(7):2144–2146.PubMedCrossRefGoogle Scholar
  51. 51.
    Boyer PL, Sarafianos SG, Arnold E, Hughes SH. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J Virol 2001;75:4832–4842.PubMedCrossRefGoogle Scholar
  52. 52.
    Chamberlain PP, Ren J, Nichols CE, et al. Crystal structures of Zidovudineor Lamivudine-resistant human immunodeficiency virus type 1 reverse transcriptases containing mutations at codons 41,184, and 215. J Virol 2002;76(19):10,015–10,019.PubMedCrossRefGoogle Scholar
  53. 53.
    Larder BA, Stammers DK. Closing in on HIV drug resistance. Nat Struct Biol. 1999;6:103–106.PubMedCrossRefGoogle Scholar
  54. 54.
    Larder BA, Kemp SD, Harrigan PR. Potential mechanism for sustained antietro-viral efficacy of AZT-3TC combination therapy. Science 1995;269:696–699.PubMedCrossRefGoogle Scholar
  55. 55.
    Larder BA. 3′-Azido-3′-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 1992;36:2664–2669.PubMedGoogle Scholar
  56. 56.
    Gotte M, Arion D, Parniak MA, Wainberg MA. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chainterminated DNA synthesis. J Virol 2000;74(8):3579–3585.PubMedCrossRefGoogle Scholar
  57. 57.
    Boyer PL, Sarafianos SG, Arnold E, Hughes SH The M184V mutation reduces the selective excision of zidovudine 5′-monophosphate (AZTMP) by the reverse transcriptase of human immunodeficiency virus type 1. J Virol 2002;76(7):3248–3256.PubMedCrossRefGoogle Scholar
  58. 58.
    Esnouf RM, Ren J, Hopkins AL, et al. Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 explain resistance mutations for this non-nucleoside inhibitor. Proc Natl Acad Sci USA 1997;94:3984–3989.PubMedCrossRefGoogle Scholar
  59. 59.
    Ren J, Nichols CE, Bird LE, et al. Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 RT involves extensive main chain hydrogen bonding. J Biol Chem. 2000;275:14,316–14,320.PubMedCrossRefGoogle Scholar
  60. 60.
    Ding J, Das K, Moereels H, et al. Structure of HIV-1 RT/TIBo R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Nat Struct Biol. 1995;2:407–415.PubMedCrossRefGoogle Scholar
  61. 61.
    Schafer W, Friebe W-G, Leinert H, et al. Non-nucleoside inhibitors of HIV-1 everse transcriptase: molecular modelling and X-ray structure investigations. J Med Chem. 1993;36(6):726–732.PubMedCrossRefGoogle Scholar
  62. 62.
    Ren J, Esnouf RM, Hopkins AL, et al. Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives. Biochemistry 1998;37:14,394–14,403.PubMedCrossRefGoogle Scholar
  63. 63.
    Yang SS, Pattabiraman N, Gussio R, Pallansch L, Buckheit RW, Bader JP. Crossresistance analysis and molecular modeling of nonnucleoside reverse transcriptase inhibitors targeting drug-resistance mutations in the reverse transcriptase of human immunodeficiency virus. Leukemia 1997;11:89–92.PubMedGoogle Scholar
  64. 64.
    Esnouf RM, Stuart DI, De Clercq E, Schwartz E, Balzarini J. Models which explain the inhibition of reverse transcriptase by HIV-1-specific (thio)carbox-anilide derivatives. Biochem Biophys Res Commun. 1997;234:458–464.PubMedCrossRefGoogle Scholar
  65. 65.
    Ren J, Esnouf RM, Hopkins AL, Stuart DI, Stammers DK. Crystallographic analysis of the binding modes of thiazoloisoindolinone non-nucleoside inhibitors to HIV-1 reverse transcriptase and comparison with modelling studies. J Med Chem. 1999;42:3845–3851.PubMedCrossRefGoogle Scholar
  66. 66.
    Spence RA, Kati WM, Anderson KS, Johnson KA. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 1995;267:988–993.PubMedCrossRefGoogle Scholar
  67. 67.
    Rittinger K, Divita G, Goody RS. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc Natl Acad Sci USA 1995;92(17):8046–8049.PubMedCrossRefGoogle Scholar
  68. 68.
    Das K, Ding J, Hsiou Y, et al. Crystal structures of 8-Cl and 9-Cl TIBo complexed with wild-type HIV-1 RT and 8-Cl TIBo complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant. J Mol Biol. 1996;264:1085–1100.PubMedCrossRefGoogle Scholar
  69. 69.
    Baba M, Shigeta S, Yuasa S, et al. Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro. Antimicrob Agents Chemother 1994;38:688–692.PubMedGoogle Scholar
  70. 70.
    Hopkins AL, Ren J, Esnouf RM, et al. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J Med Chem. 1996;39:1589–1600.PubMedCrossRefGoogle Scholar
  71. 71.
    Chan JH, Hong JS, Hunter RN 3rd, et al. 2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1. J Med Chem. 2001;44(12):1866–1882.PubMedCrossRefGoogle Scholar
  72. 72.
    Hsiou Y, Das K, Ding J, et al. HIV-1 reverse transcriptase complexed with the nonnucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance. J Mol Biol. 1998;284:313–323.PubMedCrossRefGoogle Scholar
  73. 73.
    Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK. Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Structure Fold Des 2000;8:1089–1094.PubMedCrossRefGoogle Scholar
  74. 74.
    Ren J, Nichols C, Bird L, et al. Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors. J Mol Biol. 2001;312(4):795–805.PubMedCrossRefGoogle Scholar
  75. 75.
    Hsiou Y, Ding J, Das K, et al. The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J Mol Biol. 2001;309(2):437–445.PubMedCrossRefGoogle Scholar
  76. 76.
    Lindberg J, Sigurosson S, Lowgren S, et al. Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant. Eur J Biochem 2002;269(6):1670–1677.PubMedCrossRefGoogle Scholar
  77. 77.
    Erickson J. HIV-1 protease as a target for AIDS therapy. In: ogden RC, Flexner CW, eds. Protease Inhibitors in AIDS Therapy. New York, NY: Marcel Dekker; 2001:1–26.Google Scholar
  78. 78.
    Silvestri R, Artico M, De Martino G, et al. Synthesis, biological evaluation, and binding mode of novel 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles targeted at the HIV-1 reverse transcriptase. J Med Chem. 2002;45(8):1567–1576.PubMedCrossRefGoogle Scholar
  79. 79.
    Vig P, Mao C, Venkatachalam TK, Tuel-Ahlgren L, Sudbeck EA, Uckun FM. Rational design and synthesis of phenethyl-5-bromopyridyl thiourea derivatives as potent non-nucleoside inhibitors of HIV reverse transcriptase. Bioorg Med Chem. 1998;6:1789–1797.PubMedCrossRefGoogle Scholar
  80. 80.
    Hopkins AL, Ren J, Tanaka H, et al. Design of MKC-442 (Emivirine) analogues with improved activity against drug resistant HIV mutants. J Med Chem. 1999;42:4500–4505.PubMedCrossRefGoogle Scholar
  81. 81.
    Whittle H, Morris J, Todd J, et al. HIV-2-infected patients survive longer than HIV-1-infected patients. Aids 1994;8(11):1617–1620.PubMedCrossRefGoogle Scholar
  82. 82.
    Fan N, Rank KB, Poppe SM, Tarpley WG, Sharma SK. Characterization of the p68/p58 heterodimer of human immunodeficiency virus type 2 reverse transcriptase. Biochemistry 1996;35(6):1911–1917.PubMedCrossRefGoogle Scholar
  83. 83.
    Bird LE, Chamberlain PP, Stewart-Jones G, Ren J, Stuart DI, Stammers DK. Cloning, expression, purification and crystallisation of HIV-2 reverse transcriptase. Protein Expr Purif 2003;27:8–12.CrossRefGoogle Scholar
  84. 84.
    Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK. Structure of HIV-2 reverse transcriptase at 2.35 Å resolution and the mechanism of resistance to non-nucleoside inhibitors. Proc Natl Acad Sci USA 2002;99:14,410–14,415.PubMedCrossRefGoogle Scholar
  85. 85.
    Milton J, Slater MJ, Bird AJ, et al. Biaryl acids: novel non-nucleoside inhibitors of HIV reverse transcriptase types 1 and 2. Bioorg Med Chem Lett. 1998;8: 2623–2628.PubMedCrossRefGoogle Scholar
  86. 86.
    Tisdale M, Schulze T, Larder BA, Moelling K. Mutations within the RNase H domain of human immunodeficiency virus type 1 reverse transcriptase abolish virus infectivity. J Gen Virol 1991;72 (Pt l):59–66.PubMedCrossRefGoogle Scholar
  87. 87.
    Borkow G, Fletcher RS, Barnard J, et al. Inhibition of the ribonuclease H and DNA polymerase activities of HIV-1 reverse transcriptase by N-(4-tert-butylbenzoyl)-2-hydroxy-l-naphthaldehyde hydrazone. Biochemistry 1997;36:3179–3185.PubMedCrossRefGoogle Scholar
  88. 88.
    Muller WE, Weiler BE, Charubala R, et al. Cordycepin analogues of 2′,5′-oligoad-enylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase. Biochemistry 1991;30(8):2027–2033.PubMedCrossRefGoogle Scholar
  89. 89.
    Buiser RG, DeStefano JJ, Mallaber LM, Fay PJ, Bambara RA. Requirements for the catalysis of strand transfer synthesis by retroviral DNA polymerases. J Biol Chem. 1991;266(20):13,103–13,109.PubMedGoogle Scholar
  90. 90.
    Morris MC, Robert-Hebmann V, Chaloin L, et al. A new potent HIV-1 reverse transcriptase inhibitor. A synthetic peptide derived from the interface subunit domains. J Biol Chem. 1999;274(35):24,941–24,946.PubMedCrossRefGoogle Scholar
  91. 91.
    Sluis-Cremer N, Dmitrienko GI, Balzarini J, Camarasa MJ, Parniak MA. Human immunodeficiency virus type 1 reverse transcriptase dimer destabilization by l-[Spiro[4″-amino-2″,2″-dioxo-l″,2″-oxathiole-5″,3′-[2′, 5′-bis-0-(tert-butyl-dimethylsilyl)-beta-D-ribofuranosyl]]]-3-ethylthymine. Biochemistry 2000;39(6): 1427–1433.PubMedCrossRefGoogle Scholar
  92. 92.
    Rodriguez-Barrios F, Perez C, Lobaton E, et al. Identification of a putative binding site for [2′,5′-bis-0-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3′-spiro-5′-(4′-amino-l′, 2′-oxathiole-2′, 2′-dioxide)thymine (TSAo) derivatives at the p51-p55 interface of HIV-1 reverse transcriptase. J Med Chem. 2001;44(12): 1853–1865.PubMedCrossRefGoogle Scholar
  93. 93.
    Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997;267(3):727–748.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • David K. Stammers
    • 1
  • Jingshan Ren
    • 1
  1. 1.The Wellcome Trust Centre for Human GeneticsUniversity of oxfordOxfordUK

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