What can be expected from non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections?

Reviews in Medical Virology

Volumn 6, Issue 2, 1996, Pages 97-117

  De Clercq, Erik ^a  

^a REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

2',3' DIDEOXYNUCLEOSIDE DERIVATIVE; 3 [(4,7 DICHLORO 2 BENZOXAZOLYLMETHYL)AMINO] 5 ETHYL 6 METHYL 2(1H) PYRIDONE; 3 [2 (2 BENZOXAZOLYL)ETHYL] 5 ETHYL 6 METHYL 2(1H) PYRIDONE; ABACAVIR; ACYCLIC NUCLEOSIDE; ADEFOVIR; ANILIDE; BENZIMIDAZOLE DERIVATIVE; DELAVIRDINE; DIAZEPINE DERIVATIVE; DIDANOSINE; DIPIVOXIL; EMIVIRINE; EMTRICITABINE; LAMIVUDINE; LOVIRIDE; NEVIRAPINE; NUCLEOSIDE DERIVATIVE; OXATHIIN DERIVATIVE; PROTEINASE INHIBITOR; QUINOXALINE DERIVATIVE; RALURIDINE; RNA DIRECTED DNA POLYMERASE INHIBITOR; STAVUDINE; TENOFOVIR; TIVIRAPINE; TROVIRDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZALCITABINE; ZIDOVUDINE;

DRUG CONFORMATION; DRUG POTENTIATION; DRUG RESISTANCE; DRUG STRUCTURE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN; REVIEW; SIMIAN VIRUS; STRUCTURE ACTIVITY RELATION; VIRUS INFECTION; VIRUS INHIBITION; VIRUS REPLICATION;

EID: 0029775166     PISSN: 10529276     EISSN: None     Source Type: Journal    
DOI: 10.1002/(sici)1099-1654(199606)6:2<97::aid-rmv168>3.0.co;2-4     Document Type: Review

References (162)

1. De Clercq, E. (1995). Antiviral therapy for human immunodeficiency virus infections. Clin. Microbiol. Rev. 8, 200-239.
2. De Clercq, E. (1995). Toward improved anti-HIV chemotherapy: therapeutic strategies for intervention with HIV infections. J. Med. Chem. 38, 2491-2517.
3. De Clercq, E. (1995). Trends in the development of new antiviral agents for the chemotherapy of infections caused by herpesviruses and retroviruses. Rev. Med. Virol. 5, 149-164.
4. Naesens, L., Balzarini, J. and De Clercq, E. (1994). Therapeutic potential of PMEA as an antiviral drug. Rev. Med. Virol. 4, 147-159.
5. Balzarini, J., Holy, A., Jindrich, J. et al. (1993) Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6-diaminopurine. Antimicrob. Agents Chemother. 37, 332-338.
6. Tsai, C.-C., Follis, K. E., Sabo, A. et al. (1995). Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl)adenine. Science 270, 1197-1199.
7. De Clercq, E. (1993). HIV-1-specific RT inhibitors: highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Med. Res. Rev. 13, 229-258.
8. De Clercq, E. (1994). Non-nucleoside reverse transcriptase inhibitors (NNRTIs). Exp. Opin. Invest. Drugs 3, 253-271.
9. Baba, M., Tanaka, H., De Clercq, E. et al. (1989). Highly specific inhibition of human immunodeficiency virus type 1 by a novel 6-substituted acyclouridine derivative. Biochem. Biophys. Res. Commun. 165, 1375-1381.
10. Miyasaka, T., Tanaka, H., Baba, M. et al. (1989). A novel lead for specific anti-HIV-1 agents: 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine. J. Med. Chem. 32, 2507-2509.
11. Pauwels, R., Andries, K., Desmyter, J. et al. (1990). Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 343, 470-474.
12. Debyser, Z., Pauwels, R., Andries, K. et al. (1991). An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivatives. Proc. Natl Acad. Sci. USA 88, 1451-1455.
13. Baba, M., De Clercq, E., Tanaka, H. et al. (1991). Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase. Proc. Natl Acad. Sci. USA 88, 2356-2360.
14. Baba, M., De Clercq, E., Tanaka, H. et al. (1991). Highly potent and selective inhibition of human immunodeficiency virus type 1 by a novel series of 6-substituted acyclouridine derivatives. Mol. Pharmacol. 39, 805-810.
15. Merluzzi, V. J., Hargrave, K. D., Labadia, M. et al. (1990). Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 250, 1411-1413.
16. Koup, R. A., Merluzzi, V. J., Hargrave, K. D. et al. (1991). Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by the dipyridodiazepinone BI-RG-587. J. Infect. Dis. 163, 966-970.
17. Goldman, M. E., Nunberg, J. H., O'Brien, J. A. et al. (1991). Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity. Proc. Natl Acad. Sci. USA 88, 6863-6867.
18. Goldman, M. E., O'Brien, J. A., Ruffing, T. L. et al. (1992). L.-696, 229 specifically inhibits human immunodeficiency virus type 1 reverse transcriptase and possesses antiviral activity in vitro. Antimicrob. Agents Chemother. 36, 1019-1023.
19. Romero, D. L., Busso, M., Tan, C-K. et al. (1991). Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc. Natl Acad. Sci. USA 88, 8806-8810.
20. Romero, D. L., Morge, R. A., Genin, M. J. et al. (1993). Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships of novel substituted indole analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl)carbonyl]-4-[3-[(1-methylethyl)amino] pyridinyl]piperazine monomethanesulfonate (U-90152S), a second-generation clinical candidate. J. Med. Chem. 36, 1505-1508.
21. Balzarini, J., Pérez-Pérez, M.-J., San-Félix, A. et al. (1992). 2′,5′-Bis-O-(tert-butyldimethylsilyl)-3′-spiro-5″- (4″-amino-1″,2″-oxathiole-2″,2″-dioxide)pyrimidine (TSAO) nucleoside analogues: highly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proc. Natl Acad. Sci. USA 89, 4392-4396.
22. Balzarini, J., Pérez-Pérez, M.-J., San-Félix, A., Vélazquez, S., Camarasa, M.-J. and De Clercq, E. (1992). [2́,5́-Bis-O-(tert-butyldimethylsilyl)]-3′-spiro-5″- (4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO) derivatives of purine and pyrimidine nucleosides as potent and selective inhibitors of human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 36, 1073-1080.
23. Balzarini, J., Pérez-Pérez, M.-J., San-Félix, A. et al. (1992). Kinetics of inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase by the novel HIV-1 specific nucleoside analogue [2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]- 3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″, 2″-dioxide)thymine (TSAO-T). J. Biol. Chem. 267, 11831-11838.
24. Pauwels, R., Andries, K., Debyser, Z. et al. (1993). Potent and highly selective human immunodeficiency virus type 1 (HIV-1) inhibition by a series of α-anilinophenylacetamide derivatives targeted at HIV-1 reverse transcriptase. Proc. Natl Acad. Sci. USA 90, 1711-1715.
25. De Clercq, E. (1996). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infections: strategies to overcome drug resistance development. Med. Res. Rev., 16, 125-157.
26. White, E. L., Buckheit, R. W. Jr., Ross, L. J. et al. (1991). A TIBO derivative, R82913, is a potent inhibitor of HIV-1 reverse transcriptase with heteropolymer techniques. Antiviral Res. 16, 257-266.
27. Pauwels, R., Andries, K., Debyser, Z. et al. (1994). New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiaze-pin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2′,3′-dideoxynucleoside analogs. Antimicrob. Agents Chemother. 38, 2863-2870.
28. Baba, M., Yuasa, S., Niwa, T. et al. (1993). Effect of human serum on the in vitro anti-HIV-1 activity of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives as related to their lipophilicity and serum protein binding. Biochem. Pharmacol. 45, 2507-2512.
29. Yuasa, S., Sadakata, Y, Takashima, H. et al. (1993). Selective and synergistic inhibition of human immunodeficiency virus type 1 reverse transcriptase by a non-nucleoside inhibitor, MKC-442. Mol. Pharmacol. 44, 895-900.
30. Baba, M., Shigeta, S., Yuasa, S. et al. (1994). Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro. Antimicrob. Agents Chemother. 38, 688-692.
31. Hargrave, K. D., Proudfoot, J. R., Grozinger, K. G. et al. (1991). Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyridobenzo- and dipyridodiazepinones. J. Med. Chem. 34, 2231-2241.
32. Saari, W. S., Hoffman, J. M., Wai, J. S. et al. (1991). 2-Pyridinone derivatives: a new class of nonnucleoside HIV-1-specific reverse transcriptase inhibitors. J. Med. Chem. 34, 2922-2925.
33. Dueweke, T. J., Poppe, S. M., Romero, D. L. et al. (1993). U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob. Agents Chemother. 37, 1127-1131.
34. Camarasa, M.-J., Pérez-Pérez, M.-J., San-Félix, A., Balzarini, J. and De Clercq, E. (1992). 3′-Spiro nucleosides, a new class of specific human immunodeficiency virus type inhibitors: synthesis and antiviral activity of [2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-xylo- and -ribofuranose]-3′-spiro-5″-(4″-amino-1″,2″- oxathiole-2″,2″-dioxide) (TSAO) pyrimidine nucleosides. J. Med. Chem. 35, 2721-2727.
35. Pérez-Pérez, M.-J., San-Félix, A. Balzarini, J., De Clercq, E. and Camarasa, M. J. (1992). TSAO analogues. Stereospecific synthesis and anti-HIV-1 activity of 1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]- 3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″, 2″-dioxide) pyrimidine and pyrimidine-modified nucleosides. J. Med. Chem. 35, 2988-2995.
36. Ahgren, C., Bäckbro, K., Bell, F. W. et al. (1995). The PETT series, a new class of potent nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 39, 1329-1335.
37. Zhang, H., Vrang, L., Bäckbro, K. et al. (1995). Inhibition of human immunodeficiency virus type 1 wild-type and mutant reverse transcriptases by the phenyl ethyl thiazolyl thiourea derivatives trovirdine and MSC-127. Antiviral Res. 28, 331-342.
38. Bader, J. P., McMahon, J. B., Schultz, R. J. et al. (1991). Oxathiin carboxanilide, a potent inhibitor of human immunodeficiency virus reproduction. Proc. Natl Acad. Sci. USA 88, 6740-6744.
39. Baizarini, J., Jonckheere, H., Harrison, W. A. et al. (1995). Oxathiin carboxanilide derivatives: a class of non-nucleoside HIV-1 specific reverse transcriptase inhibitors (NNRTIs) that are active against mutant HIV-1 strains resistant to other NNRTIs. Antiviral Chem. Chemother. 6, 169-178.
40. Balzarini, J., Brouwer, W. G., Felauer, E. E., De Clercq, E. and Karlsson, A. (1995). Activity of various thiocarboxanilide derivatives against wild-type and several mutant human immunodeficiency virus type 1 strains. Antiviral Res. 27, 219-236.
41. Balzarini, J., Pelemans, H., Aquaro, S., Perno, C.-F., Witvrouw, M., Schols, D., De Clercq, E. and Karlsson, A. (1996). Highly favorable antiviral activity and resistance profile of the novel thiocarboxanilide pentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. Mol. Pharmacol., in press.
42. Kleim, J.-P., Bender, R., Billhardt, U.-M. et al. (1993). Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication. Antimicrob. Agents Chemother. 37, 1659-1664.
43. Kleim, J.-P., Bender, R., Kirsch, R. et al. (1995). Preclinical evaluation of HBY 097, a new nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication. Antimicrob. Agents Chemother. 39, 2253-2257.
44. Buckheit R. W. Jr., Hollingshead, M. G., Germany-Decker, J. et al. (1993). Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor. Antiviral Res. 21, 247-265.
45. Mertens, A., Zilch, H., König, B. et al. (1993). Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo [2,3a]isoindol-5(9bH)-ones and related compounds with anti-HIV-1 activity. J. Med. Chem. 36, 2526-2535.
46. Maass, G., Immendoerfer, U., Koenig, B. et al. (1993). Viral resistance to the thiazolo-iso-indolinones, a new class of nonnucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 37, 2612-2617.
47. Williams, T. M., Ciccarone, T. M., MacTough, S. C. et al. (1993). 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: a novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J. Med. Chem. 36, 1291-1294.
48. Dollé, V., Nguyen, C. H., Aubertin, A.-M. et al. (1995). A new series of pyridinone derivatives as potent non-nucleoside human immunodeficiency virus type 1 specific reverse transcriptase inhibitors. J. Med. Chem. 38, 4679-4686.
49. Artico, M., Massa, S., Mai, A. et al. (1993). 3,4-Dihydro-2-alkoxy-6-benyzl-4-oxopyrimidines (DABOs): a new class of specific inhibitors of human immunodeficiency virus type .1. Antiviral Chem. Chemother. 4, 361-368.
50. Massa, S., Mai, A., Artico, M. et al. (1995). Synthesis and antiviral activity of new 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs), specific inhibitors of human immunodeficiency virus type 1. Antiviral Chem. Chemother. 6, 1-8.
51. Buckheit, R. W. Jr., Fliakas-Boltz, V., Decker, W. D. et al. (1994). Biological and biochemical anti-HIV activity of the benzothiadiazine class of nonnucleoside reverse transcriptase inhibitors. Antiviral Res. 25, 43-56.
52. Tucker, T. J., Lyle, T. A., Wiscount, C. M. et al. (1994). Synthesis of a series of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2 (1H)-ones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors. J. Med. Chem. 37, 2437-2444.
53. Ijichi, K., Fujiwara, M., Hanasaki, Y. et al. (1995). Potent and specific inhibition of human immunodeficiency virus type 1 replication by 4-(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-Y1 N,N-dialkylcarbamate derivatives. Antimicrob. Agents Chemother. 39, 2337-2340.
54. Bellarosa, D., Antonelli, G., Bambacioni, F. et al. (1996). New arylpyrido-diazepine and -thiodiazepine derivatives are potent and highly selective HIV-1 inhibitors targeted at the reverse transcriptase. Antiviral Res., in press.
55. Kashman, Y., Gustafson, K. R., Fuller, R. W. et al. (1992). The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllum lanigernum. J. Med. Chem. 35, 2735-2743.
56. Patil, A. D., Freyer, A. J., Eggleston, D. S. et al. (1993). The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum linn. J. Med. Chem. 36, 4131-4138.
57. De Lucca, G. V. and Otto, M. J. (1992). Synthesis and anti-HIV activity of pyrrolo-[1,2-d]-(1,4)-benzodiazepin-6-ones. Bioorg. Med. Chem. Lett. 2, 1639-1644.
58. Terrett, N. K., Bojanic, D., Merson, J. R. et al. (1992). Imidazo[2′,3′:6,5]dipyrido[3,2-b:2′,3′-e]-1,4- diazepines: non-nucleoside HIV-1 reverse transcriptase inhibitors with greater enzyme affinity than nevirapine. Bioorg. Med. Chem. Lett. 2, 1745-1750.
59. Livermore, D. G. H., Bethell, R. C., Cammack, N. et al. (1993). Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines. J. Med. Chem. 36, 3784-3794.
60. Antonucci, T., Warmus, J. S.,. Hodges, J. C. and Nickell, D. G. (1995). Characterization of the antiviral activity of highly substituted pyrroles: a novel class of non-nucleoside HIV-1 reverse transcriptase inhibitor. Antiviral Chem. Chemother. 6, 98-108.
61. McMahon, J. B., Gulakowski, R. J., Weislow, O. S. et al. (1993). Diarylsulfones, a new chemical class of nonnucleoside antiviral inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 37, 754-760.
62. Alam, M., Bechtold, C. M., Patick, A. K. et al. (1993). Substituted naphthalenones as a new structural class of HIV-1 reverse transcriptase inhibitors. Antiviral Res. 22, 131-141.
63. Artico, M., Stefancich, G., Silvestri, R. et al. (1994). Pyrrolobenzothiazepines: a new class of nonnucleoside HIV-1 reverse transcriptase inhibitors. Med. Chem. Res. 4, 283-290.
64. Mui, P. W., Jacober, S. P., Hargrave, K. D. and Adams, J. (1992). Crystal structure of nevirapine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, and computational alignment with a structurally diverse inhibitor. J. Med. Chem. 35, 201-202.
65. Chimirri, A., Grasso, S., Monforte, A. M., Monforte, P. and Zappalà, M. (1995). Thiazobenzimidazoles as non-nucleoside HIV-1 RT inhibitors. Abstracts of the II Congresso Congiunto Italiano-Spagnolo di Chimica Farmaceutica, Ferrara, Italy, August 30-September 3, 1995, ML20.
66. Ren, J., Esnouf, R., Hopkins, A. et al. (1995). The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design. Structure 3, 915-926.
67. Kroeger-Smith, M. B., Rouzer, C. A., Taneyhill, L. A. et al. (1995). Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors: total energy of complexation as a predictor of drug placement and activity. Protein Sci. 4, 2203-2222.
68. Ding, J., Das, K., Tantillo, C. et al. (1995). Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α-APA R95845 at 2.8 A resolution. Structure 3, 365-379.
69. Ding, J., Das, K., Moereels, H. et al. (1995). Structure of HIV-1 RT/TIBO R86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors. Structural Biol. 2, 407-415.
70. Tramontano, E. and Cheng, Y.-C. (1992). HIV-1 reverse transcriptase inhibition by a dipyrido-diazepinone derivative: BI-RG-587. Biochem. Pharmacol. 43, 1371-1376.
71. Althaus, I. W., Chou, J. J., Gonzales, A. J. et al. (1993). Steady-state kinetic studies with the nonnucleoside HIV-1 reverse transcriptase inhibitor U-87201E. J. Biol. Chem. 268, 6119-6124.
72. Frank, K. B., Noll, G. J., Connell, E. V. and Sim, I. S. (1991). Kinetic interaction of human immunodeficiency virus type 1 reverse transcriptase with the antiviral tetrahydroimidazo[4,5,1-jk]-[1,4]benzodiazepine-2-(1H)-thione compound, R82150. J. Biol. Chem. 266, 14232-14236.
73. Kopp, E. B., Miglietta, J. J., Shrutkowski, A. G., Shih, C.-K., Grob, P. M. and Skoog, M. T. (1991). Steady state kinetics and inhibition of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template. Nucleic Acids Res. 19, 3035-3039.
74. Debyser, Z., Vandamme, A.-M., Pauwels, R., Baba, M., Desmyter, J. and De Clercq, E. (1992). Kinetics of inhibition of endogenous human immunodeficiency virus type 1 reverse transcription by 2′,3′-dideoxynucleoside 5′-triphosphate, tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione, and l-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-thymine derivatives. J. Biol. Chem. 267, 11769-11776.
75. Debyser, Z., Pauwels, R., Andries, K. et al. (1992). Allosteric inhibition of human immunodeficiency virus type 1 reverse transcriptase by tetra-hydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione compounds. Mol Pharmacol. 41, 203-208.
76. Wu, J. C., Warren, T. C., Adams, J. et al. (1991). A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a nonsubstrate binding site. Biochemistry 30, 2022-2026.
77. Debyser, Z., Pauwels, R., Baba, M., Desmyter, J. and De Clercq, E. (1992). Common features in the interaction of tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione and 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives with the human immunodeficiency virus type 1 reverse transcriptase. Mol Pharmacol. 41, 963-968.
78. Debyser, Z., De Vreese, K., Pauwels, R. et al. (1992). Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus. J. Gen. Virol. 73, 1799-1804.
79. Spence, R. A., Kati, W. M., Anderson, K. S. and Johnson, K. A. (1995). Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 267, 988-993.
80. Cohen, K. A., Hopkins, J., Ingraham, R. H. et al. (1991). Characterization of the binding site for nevirapine (BI-RG-587), a nonnucleoside inhibitor of human immunodeficiency virus type-1 reverse transcriptase. J. Biol. Chem. 266, 14670-14674.
81. Shih, C-K., Rose, J. M., Hansen, G. L., Wu, J. C., Bacolla, A. and Griffin, J. A. (1991). Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptase display reversed sensitivity to non-nucleoside analog inhibitors. Proc. Natl Acad. Sci. USA 88, 9878-9882.
82. De Vreese, K., Debyser, Z., Vandamme, A.-M. et al. (1992). Resistance of human immunodeficiency virus type 1 reverse transcriptase to TIBO derivatives induced by site-directed mutagenesis. Virology 188, 900-904.
83. Condra, J. H., Emini, E. A., Gotlib, L. et al. (1992). Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors. Antimicrob. Agents Chemother. 36, 1441-1446.
84. Hizi, A., Shaharabany, M., Currens, M. J., Boyd, M. R., Hughes, S. H. and McMahon, J. B. (1993). Specific inhibition of the reverse transcriptase of human immunodeficiency virus type 1 and the chimeric enzymes of human immunodeficiency virus type 1 and type 2 by nonnucleoside inhibitors. Antimicrob. Agents Chemother. 37, 1037-1042.
85. Arnold, E., Jacobo-Molina, A., Nanni, R. G. et al. (1992). Structure of HIV-1 reverse transcriptase/ DNA complex at 7 Å resolution showing active site locations. Nature 357, 85-89.
86. Kohlstaedt, L. A., Wang, J., Friedman, J. M., Rice, P. A. and Steitz, T. A. (1992). Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256, 1783-1790.
87. Jacobo-Molina, A., Ding., J. Nanni, R. G. et al. (1993). 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 90, 6320-6324.
88. Unge, T., Knight, S., Bhikhabhai, R. et al. (1994). 2.2. Å resolution structure of the amino-terminal half of HIV-1 reverse transcriptase (fingers and palm subdomains). Structure 2, 953-961.
89. Ren, J., Esnouf, R., Garman, E. et al. (1995). High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Structural Biol. 2, 293-302.
90. Nanni, R. G., Ding, J., Jacobo-Molina, A., Hughes, S. H. and Arnold, E. (1993). Review of HIV-1 reverse transcriptase three-dimensional structure: implications for drug design. Perspect. Drug Discov. Design 1, 129-150.
91. Tantillo, C., Ding, J., Jacobo-Molina, A. et al. (1994). Locations of anti-AIDS drug binding sites and resistance mutations in the three-dimensional structure of HIV-1 reverse transcriptase. Implications for mechanisms of drug inhibition and resistance. J. Mol. Biol. 243, 369-387.
92. Esnouf, R., Ren, J., Ross, C., Jones, Y., Stammers, D. and Stuart, D. (1995). Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Structural Biol. 2, 303-308.
93. Rodgers, D. W., Gamblin, S. J., Harris, B. A. et al. (1995). The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc Natl Acad. Sci. USA 92, 1222-1226.
94. Patel, P. H., Jacobo-Molina, A., Ding, J. et al. (1995). Insights into DNA polymerization mechanisms from structure and function analysis of HIV-1 reverse transcriptase. Biochemistry 34, 5351-5363.
95. Nunberg, J. H., Schleif, W. A., Boots, E. J. et al. (1991). Viral resistance to human immunodeficiency virus type-1 specific pyridinone reverse transcriptase inhibitors. J. Virol. 65, 4887-4892.
96. Richman, D., Shih, C.-K., Lowy, I. et al. (1991). Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc. Natl Acad. Sci. USA 88, 11241-11245.
97. Mellors, J. W., Dutschman, G. E., Im, G.-J., Tramontane, E., Winkler, S. R. and Cheng, Y.-C. (1992). In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase. Mol. Pharmacol. 41, 446-451.
98. Mellors, J. W., Im, G.-J., Tramontano, E. et al. (1993). A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo [4,5,1-jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150). Mol. Pharmacol. 43, 11-16.
99. Balzarini, J., Karlsson, A., Pérez-Pérez, M.-J. et al. (1993). HIV-1 specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase. Virology 192, 246-253.
100. Balzarini, J., Vélazquez, S., San-Félix, A. et al. (1993). Human immunodeficiency virus type 1-specific [2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]- 3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″, 2″-dioxide)-purine analogues show a resistance spectrum that is different from that of the human immunodeficiency virus type 1-specific non-nucleoside analogues. Mol. Pharmacol. 43, 109-114.
101. Balzarini, J., Karlsson, A., Vandamme, A.-M. et al. (1993). Human immunodeficiency virus type 1 (HIV-1) strains selected for resistance against the HIV-1 specific [2′,5′-bis-O-(tert-butyldimethylsilyl)-3′-spiro-5″- (4″-amino-1″,2″-oxathiole-2″,2″-dioxide)]-β- D-pentofuranosyl (TSAO) nucleoside analogues retain sensitivity to HIV-1-specific nonnucleoside inhibitors. Proc. Natl Acad. Sci. USA 90, 6952-6956.
102. Balzarini, J., Karlsson, A. and De Clercq, E. (1993). Human immunodeficiency virus type 1 drug-resistance patterns with different 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives. Mol. Pharmacol. 44, 694-701.
103. Seki, M., Sadakata, Y., Yuasa, S. and Baba, M. (1995). Isolation and characterization of human immunodeficiency virus type-1 mutants resistant to the non-nucleotide reverse transcriptase inhibitor MKC-442. Antiviral Chem. Chemother. 6, 73-79.
104. Buckheit, R. W. Jr., Fliakas-Boltz, V., Yeagy-Bargo, S. et al. (1995). Resistance to 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives is generated by mutations at multiple sites in the HIV-1 reverse transcriptase. Virology 210, 186-193.
105. Dueweke, T. J., Pushkarskaya, T., Poppe, S. M. et al. (1993). A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc. Natl. Acad. Sci. USA 90, 4713-4717.
106. Kleim, J.-P., Bender, R., Kirsch, R., Meichsner, C., Paessens, A. and Riess, G. (1994). Mutational analysis of residue 190 of human immunodeficiency virus type 1 reverse transcriptase. Virology 200, 696-701.
107. Balzarini, J., Pérez-Pérez, M.-J., Vélazquez, S. et al. (1995). Suppression of the breakthrough of human immunodeficiency virus type 1 (HIV-1) in cell culture by thiocarboxanilide derivatives when used individually or in combination with other HIV-1 specific inhibitors (i.e. TSAO derivatives). Proc. Natl. Acad. Sci. USA 92, 5470-5474.
108. Balzarini, J., Karlsson, A., Sardana, V. V., Emini, E. A., Camarasa, M.-J. and De Clercq, E. (1994). Human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors may suppress the replication of specific drug-resistant (E138K) RT HIV-1 mutants or select for highly resistant (Y181 C→C1811) RT HIV-1 mutants. Proc. Natl. Acad. Sci. USA 91, 6599-6603.
109. Mellors, J. W., Larder, B. A. and Schinazi, R. F. (1995). Mutations in HIV-1 reverse transcriptase and protease associated with drug resistance. Int. Antiviral News 3, 8-13.
110. 138→Lys on the p51 subunit. J. Biol. Chem. 269, 25255-25258.
111. Boyer, P. L., Ding, J., Arnold, E. and Hughes, S. H. (1994). Subunit specificity of mutations that confer resistance to nonnucleoside inhibitors in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 38, 1909-1914.
112. Boyer, P. L., Currens, M. J., McMahon, J. B., Boyd, M. R. and Hughes, S. H. (1993). Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase. J. Virol. 67, 2412-2420.
113. Sardana, V. V., Emini, E. A., Gotlib, L. et al. (1992). Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J. Biol. Chem. 267, 17526-17530.
114. Byrnes, V. W., Sardana, V. V., Schleif, W. A. et al. (1993). Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob. Agents Chemother. 37, 1576-1579.
115. Zhang, H., Vrang, L., Unge, T. and Öberg, B. (1993). Characterization of HIV reverse transcriptases with Tyr181→Cys and Leu100→Ile mutations. Antiviral Chem. Chemother. 4, 301-308.
116. Zhang, H., Vrang, L., Bäckbro, K., Unge, T., Noréen, R. and Öberg, B. (1994). Enzymatic properties and sensitivity to inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase with Glu-138→Arg and Tyr-188→His mutations. Antiviral Res. 24, 43-57.
117. Richman, D. D., Havlir, D., Corbeil, J. et al. (1994). Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J. Virol. 68, 1660-1666.
118. Saag, M. S., Emini, E. A., Laskin, O. L. et al. (1993). A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. New Engl J. Med. 329, 1065-1072.
119. Demeter, L. M., Shafer, R. W., Para, M. et al. (1995). Delavirdine (DLV) susceptibility of HIV-1 isolates obtained from patients (PTS) receiving DLV monotherapy (ACTG 260). Abstracts of the Fourth International Workshop on HIV Drug-Resistance, Sardinia, Italy, July 6-9, 1995, p. 23.
120. Pialoux, G., Youle, M., Dupont, B. et al. (1991). Pharmacokinetics of R 82913 in patients with AIDS or AIDS-related complex. Lancet 338, 140-143.
121. Vandamme, A.-M., Debyser, Z., Pauwels, R. et al. (1994). Characterization of HIV-1 strains isolated from patients treated with TIBO R82913. AIDS Res. Human Retrovir. 10, 39-46.
122. Moeremans, M., De Raeymaeker, M., Van den Broeck, R. et al. (1995). Virological analysis of HIV-1 isolates in patients treated with the non-nucleoside reverse transcriptase inhibitor RO91767, (-)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5, 1-jk][1,4]benzodiazepine-2(1H)-thione monohydrochloride (8-chloro-TIBO). Abstracts of the Fourth International Workshop on HIV Drug-Resistance, Sardinia, Italy, July 6-9, 1995, p. 33.
123. Moeremans, M., De Raeymaeker, M., Van den Broeck, R., Stoffels, P. and Andries, K. (1995). Genotypic analysis of HIV-1 isolates from patients receiving loviride alone, or in combination with nucleoside reverse transcriptase inhibitors. Abstracts of the Fourth International Workshop on HIV Drug-Resistance, Sardinia, Italy, July 6-9, 1995, p. 34.
124. Schmit, J. C., Cogniaux, J., Hermans, P. et al. (1995). Multiple drug resistance mutations against nucleoside analogues and non-nucleoside specific RT inhibitors (NNRTI) in a highly replicating HIV-1 strain. Abstracts of the Fourth International Workshop on HIV Drug-Resistance, Sardinia, Italy, July 6-9, 1995, p. 24.
125. De Clercq, E. (1994). HIV resistance to reverse transcriptase inhibitors. Biochem. Pharmacol. 47, 155-169.
126. De Clercq, E. (1994). Resistance of human immunodeficiency virus type 1 (HIV-1) to non-nucleoside HIV-1 specific reverse transcriptase inhibitors. Int. J. Immunother. 10, 145-158.
127. Smerdon, S. J., Jäger, J., Wang, J. et al. (1994). Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type I. Proc. Natl. Acad. Sci. USA 91, 3911-3915.
128. Balzarini, J., Karlsson, A., Meichsner, C. et al. (1994). Resistance pattern of human immunodeficiency virus type 1 reverse transcriptase to quinoxaline S-2720. J. Virol. 68, 7986-7992.
129. Balzarini, J., Baba, M. and De Clercq, E. (1995). Differential activities of 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio)thymine derivatives against different human immunodeficiency virus type 1 mutant strains. Antimicrob. Agents Chemother. 39, 998-1002.
130. Goldman, M. E., O'Brien, J. A., Ruffing, T. L. et al. (1993). A nonnucleoside reverse transcriptase inhibitor active on human immunodeficiency virus type 1 isolates resistant to related inhibitors. Antimicrob. Agents Chemother. 37, 947-949.
131. Proudfoot, J. R., Hargrave, K. D., Kapadia, S. R. et al. (1995). Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodiazepinones as potent inhibitors of both wild-type and cysteine-181 HIV-1 reverse transcriptase enzymes. J. Med. Chem. 38, 4830-4838.
132. Kelly, T. A., Proudfoot, J. R., McNeil, D. W. et al. (1995). Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 5. 4-Substituted and 2,4-disubstituted analogs of nevirapine. J. Med. Chem. 38, 4839-4847.
133. Buckheit, R. W. Jr., White, E. L., Germany-Decker, J. et al. (1994). Cell-based and biochemical analysis of the anti-HIV activity of combinations of 3′-azido-3′-deoxythymidine and analogues of TIBO. Antiviral Chem. Chemother. 5, 35-42.
134. Baba, M., Ito, M., Shigeta, S. et al. (1991). Synergistic inhibition of human immunodeficiency virus type 1 replication by 5-ethyl-1-ethoxymethyl-6-(phenylthio)uracil (E-EPU) and azidothymidine in vitro. Antimicrob. Agents Chemother. 35, 1430-1433.
135. Brennan, T. M., Taylor, D. L., Bridges, C. G., Leyda, J. P. and Tyms, A. S. (1995). The inhibition of human immunodeficiency virus type 1 in vitro by a
136. Richman, D., Rosenthal, A. S., Skoog, M. et al. (1991). BI-RG-587 is active against zidovudine-resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob. Agents Chemother. 35, 305-308.
137. Campbell, T. B., Young, R. K., Eron, J. J., D'Aquila, R. T., Tarpley, W. G. and Kuritzkes, D. R. (1993). Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperazine atevirdine (U-87201E) in combination with zidovudine or didanosine. J. Infect. Dis. 168, 318-326.
138. Chong, K.-T., Pagano, P.-J. and Hinshaw, R. R. (1994). Bisheteropiperazine reverse transcriptase inhibitor in combination with 3′-azido-3′-deoxythymidine or 2′,3′-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro. Antimicrob. Agents Chemother. 38, 288-293.
139. Chow, Y.-K, Hirsch, M. S., Merrill, D. P. et al. (1993) Use of evolutionary limitations of HIV-1 multidrug resistance to optimize therapy. Nature 361, 650-654.
140. Larder, B. A., Kellam, P. and Kemp, S. D. (1993). Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. Nature 365, 451-453.
141. Emini, E. A., Graham, D. J., Gotlib, L., Condra, J. H., Byrnes, V. W. and Schleif, W. A. (1993). HIV and multidrug resistance. Nature 364, 679.
142. Larder, B. A. (1992). 3′-Azido-3′-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 36, 2664-2669.
143. Tisdale, M., Kemp, S. D., Parry, N. R. and Larder, B. A. (1993). 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 90, 5653-5656.
144. Byrnes, V. W., Emini, E. A., Schleif, W. A. et al. (1994). Susceptibilities of human immunodeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 38, 1404-1407.
145. Balzarini, J., Pelemans, H., Pérez-Pérez, M.-J. et al. (1996). Highly increased activity of TSAO, carboxanilide, BHAP and HEPT derivatives against human immunodeficiency virus type 1, when combined with (-)2′,3′-dideoxy-3′-thiacytidine (3TC). Mol. Pharmacol., in press.
146. Balzarini, J., Karlsson, A., Pérez-Pérez, M.-J., Camarasa, M.-J., Tarpley, W. G. and De Clercq, E. (1993). Treatment of human immunodeficiency virus type 1 (HIV-1)-infected cells with combinations of HIV-1 specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy. J. Virol. 67, 5353-5359.
147. Balzarini, J., Karlsson, A., Pérez-Pérez, M.-J., Camarasa, M.-J. and De Clercq, E. (1993). Knocking-out concentrations of HIV-1 specific inhibitors completely suppress HIV-1 infection and prevent the emergence of drug-resistant virus. Virology 196, 576-585.
148. Vasudevachari, M. B., Battista, C., Lane, H. C. et al. (1992). Prevention of the spread of HIV-1 infection with nonnucleoside reverse transcriptase inhibitors. Virology 190, 269-277.
149. Nitschko, H., Lindhofer, H., Schätzl, H. et al. (1994). Long-term treatment of HIV-infected MT-4 cells in culture with HIV proteinase inhibitor Ro 31-8959 leads to complete cure of infection. Antiviral Chem. Chemother. 5, 236-242.
150. Smith, M. S., Brian, E. L. and Pagano, J. S. (1987). Resumption of virus production after human immunodeficiency virus infection of T lymphocytes in the presence of azidothymidine. J. Virol. 61, 3769-3773.
151. Balzarini, J., Weeger, M., Camarasa, M.-J., De Clercq, E. and Uberla, K. (1995). Sensitivity/ resistance profile of a simian immunodeficiency virus containing the reverse trancriptase gene of human immunodeficiency virus type 1 (HIV-1) toward the HIV-1-specific non-nucleoside reverse transcriptase inhibitors. Biochem. Biophys. Res. Commun. 211, 850-856.
152. De Wit, S., Hermans, P., Sommereijns, B. et al. (1992). Pharmacokinetics of R 82913 in AIDS patients: a phase I dose-finding study of oral administration compared with intravenous infusion. Antimicrob. Agents Chemother. 36, 2661-2663.
153. Cheeseman, S. H., Hattox, S. E., McLaughlin, M. M. et al. (1993). Pharmacokinetics of nevirapine: initial single-rising-dose study in humans. Antimicrob. Agents Chemother. 37, 178-182.
154. Davey, R. T. Jr., Dewar, R. L., Reed, G. F. et al. (1993). Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661. Proc. Natl. Acad. Sci. USA 90, 5608-5612.
155. De Brabander, M., Staszewski, S., Roels, V. et al. (1994). Double blind evaluation of the effects of R 18893, loviride (R 89439) and placebo on immunological parameters in asymptomatic HIV seropositive subjects. Abstracts of the Tenth International Conference on AIDS, Yokohama, Japan, August 7-12, 1994, no. PB0242.
156. Wei, X, Ghosh, S. K., Taylor, M. E. et al. (1995). Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117-122.
157. Ho, D. H., Neumann, A. U., Perelson, A. S., Chen, W., Leonard, J. M. and Markowitz, M. (1995). Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature 373, 123-126.
158. Coffin, J. M. (1995). HIV population dynamics in vivo: implications for genetic variation, pathogenesis and therapy. Science 267, 483-489.
159. Nájera, I., Holguín, A., Quinones-Mateu, M. E. et al. (1995). pol Gene quasispecies of human immunodeficiency virus: mutations associated with drug resistance in virus from patients undergoing no drug therapy. J. Virol. 69, 23-31.
160. Havlir, D. V., Johnson, V. A., Hall, D. B., Robinson, P. A., Overbay, C. B. and Richman, D. D. (1995). Factors determining sustained antiviral response to nevirapine. Abstracts of the Fourth International Workshop on HIV-Drug Resistance, Sardinia, Italy, July 6-9, 1995, p. 22.
161. Schapiro, J. M., Winters, M. and Merigan, T. C. (1995). Mutational analysis of the saquinavir high dose monotherapy study. Abstracts of the Fourth International Workshop on HIV Drug-Resistance, Sardinia, Italy, 6-9, 1995, p. 73.
162. Norbeck, D., Hsu, A., Granneman, R. et al. (1995). Virologic and immunologic response to ritonavir (ABT-538), an inhibitor of HIV protease. Abstracts of the Fourth International Workshop on HIV-Drug Resistance, Sardinia, Italy, July 6-9, 1995, p. 70.