Crystallography and the design of anti-AIDS drugs: Conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors

Progress in Biophysics and Molecular Biology

Volumn 88, Issue 2, 2005, Pages 209-231

  Das, Kalyan ^a   Lewi, Paul J ^b   Hughes, Stephen H ^c   Arnold, Eddy ^a  

^a State University of New Jersey   (United States)

^b Center for Molecular Design   (Belgium)

^c NATIONAL CANCER INSTITUTE   (United States)

Author keywords

Dapivirine; Drug design; Drug resistance; Etravirine; TMC120 R147681; TMC125 R165335

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ADAPTATION; ANIMAL; CHEMISTRY; CRYSTALLOGRAPHY; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG EFFECT; ENZYMOLOGY; GENE EXPRESSION REGULATION; GENETIC VARIABILITY; GENETICS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; METABOLISM; METHODOLOGY; MULTIDRUG RESISTANCE; PHYSIOLOGY; PROTEIN CONFORMATION; REVIEW; STRUCTURE ACTIVITY RELATION; VIROLOGY;

ACQUIRED IMMUNODEFICIENCY SYNDROME; ADAPTATION, PHYSIOLOGICAL; ANIMALS; ANTI-HIV AGENTS; CRYSTALLOGRAPHY; DRUG DELIVERY SYSTEMS; DRUG DESIGN; DRUG RESISTANCE, MULTIPLE, VIRAL; GENE EXPRESSION REGULATION, VIRAL; HIV-1; HIV-1 REVERSE TRANSCRIPTASE; HUMANS; PROTEIN CONFORMATION; REVERSE TRANSCRIPTASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; VARIATION (GENETICS);

HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 9744258219     PISSN: 00796107     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pbiomolbio.2004.07.001     Document Type: Review

References (64)

1. Andries, K., de Bethune, M.-P., Ludovici, D., Kukla, M., Azijn, H., Lewi, P., Janssen, P.A.J., Pauwels, R., 2000. R165335-TMC125, a novel non nucleoside reverse transcriptase inhibitor (NNRTI) with nanomolar activity against NNRTI resistant HIV strains. In: Proceedings of the 40th ICAAC, Toronto, Canada.
2. A.T. Brunger, P.D. Adams, and L.M. Rice Recent developments for the efficient crystallographic refinement of macromolecular structures Curr. Opin. Struct. Biol. 8 1998 606 611
3. J.M. Coffin HIV population dynamics in vivo implications for genetic variation, pathogenesis, and therapy Science 267 1995 483 489
4. J.M. Coffin, S.H. Hughes, and H.E. Varmus Retroviruses 1997 Cold Spring Harbor Laboratory Press Plainview, NY
5. J. Cohen Therapies. Raising the limits Science 296 2002 2322
6. K. Das, J. Ding, Y. Hsiou, A.D. Clark Jr., H. Moereels, L. Koymans, K. Andries, R. Pauwels, P.A. Janssen, P.L. Boyer, P. Clark, R.H. Smith Jr., M.B. Kroeger Smith, C.J. Michejda, S.H. Hughes, and E. Arnold 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. 264 1996 1085 1100
7. K. Das, A.D. Clark Jr., P.J. Lewi, J. Heeres, M.R. de Jonge, L.M.H. Koymans, H.M. Vinkers, F. Daeyaert, D.W. Ludovici, M.J. Kukla, B. De Corte, R.W. Kavash, C.Y. Ho, H. Ye, M.A. Lichtenstein, K. Andries, R. Pauwels, M.-P. de Béthune, P.L. Boyer, P. Clark, S.H. Hughes, P.A.J. Janssen, and E. Arnold Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (Etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants J. Med. Chem. 47 2004 2550 2560
8. E. De Clercq Highlights in the development of new antiviral agents Mini Rev. Med. Chem. 2 2002 163 175
9. E. De Clercq New anti-HIV agents and targets Med. Res. Rev. 22 2002 531 565
10. S. Di Fabio, J. Van Roey, G. Giannini, G. van den Mooter, M. Spada, A. Binelli, M.F. Pirillo, E. Germinario, F. Belardelli, M.P. de Béthune, and S. Vella Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel formulation AIDS 17 2003 1597 1604
11. J. Ding, K. Das, H. Moereels, L. Koymans, K. Andries, P.A. Janssen, S.H. Hughes, and E. Arnold Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors Nat. Struct. Biol. 2 1995 407 415
12. J. Ding, K. Das, C. Tantillo, W. Zhang, A.D. Clark Jr., S. Jessen, X. Lu, Y. Hsiou, A. Jacobo-Molina, and K. Andries Structure of HIV-1 reverse transcriptase in a complex with the non-nucleoside inhibitor α -APA R 95845 at 2.8 Å resolution Structure 3 1995 365 379
13. J. Ding, K. Das, Y. Hsiou, S.G. Sarafianos, A.D. Clark Jr., A. Jacobo-Molina, C. Tantillo, S.H. Hughes, and E. Arnold Structure and functional implications of the polymerase 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 Å resolution J. Mol. Biol. 284 1998 1095 1111
14. R. Esnouf, J. Ren, C. Ross, Y. Jones, D. Stammers, and D. Stuart Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors Nat. Struct. Biol. 2 1995 303 308
15. R.M. Esnouf, J. Ren, A.L. Hopkins, C.K. Ross, E.Y. Jones, D.K. Stammers, and D.I. Stuart 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 nonnucleoside inhibitor Proc. Natl. Acad. Sci. USA 94 1997 3984 3989
16. Gazzard, B., Pozniak, A., Arasteh, K., Staszwski, S., Rozenbaum, W., Yeni, P., van 't Klooster, G., De Dier, K., Peeters, M., de Béthune, M.P., Graham, N. Pauwels, R., 2002. TMC125, a next-generation NNRTI, demonstrates high potency after 7 days therapy in treatment-experienced HIV-1-infected individuals with phenotypic NNRTI resistance. In: Proceedings of the Ninth Conference on Retroviruses and Opportunistic Infections, Seattle.
17. Gruzdev, B., Horban, A., Boron-Kaczmarska, A., Gille, D., Van't Klooster, G., Pauwels, R., 2001. TMC120, a new non-nucleoside reverse transcriptase inhibitor, is a potent antiretroviral in treatment naive, HIV-1 infected subjects. In: Proceedings of the Eighth Conference on Retroviruses and Opportunistic Infections, Chicago.
18. B. Gruzdev, A. Rakhmanova, E. Doubovskaya, A. Yakovlev, M. Peeters, A. Rinehart, K. De Dier, P.B. Dijk, W. Parys, and G. Van't Klooster A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects AIDS 17 2003 2487 2494
19. K. Hertogs, M.P. de Bethune, V. Miller, T. Ivens, P. Schel, A. Van Cauwenberge, C. Van Den Eynde, V. Van Gerwen, H. Azijn, M. Van Houtte, F. Peeters, S. Staszewski, M. Conant, S. Bloor, S. Kemp, B. Larder, and R. Pauwels A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs Antimicrob. Agents Chemother. 42 1998 269 276
20. D.D. Ho, A.U. Neumann, A.S. Perelson, W. Chen, J.M. Leonard, and M. Markowitz Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection Nature 373 1995 123 126
21. M. Hogberg, C. Sahlberg, P. Engelhardt, R. Noreen, J. Kangasmetsa, N.G. Johansson, B. Oberg, L. Vrang, H. Zhang, B.L. Sahlberg, T. Unge, S. Lovgren, K. Fridborg, and K. Backbro 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. 42 1999 4150 4160
22. A.L. Hopkins, J. Ren, R.M. Esnouf, B.E. Willcox, E.Y. Jones, C. Ross, T. Miyasaka, R.T. Walker, H. Tanaka, D.K. Stammers, and D.I. Stuart 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. 39 1996 1589 1600
23. Y. Hsiou, J. Ding, K. Das, A.D. Clark Jr., S.H. Hughes, and E. Arnold Structure of unliganded HIV-1 reverse transcriptase at 2.7 Å resolution implications of conformational changes for polymerization and inhibition mechanisms Structure 4 1996 853 860
24. Y. Hsiou, K. Das, J. Ding, A.D. Clark Jr., J.P. Kleim, M. Rosner, I. Winkler, G. Riess, S.H. Hughes, and E. Arnold Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097 inhibitor flexibility is a useful design feature for reducing drug resistance J. Mol. Biol. 284 1998 313 323
25. Y. Hsiou, J. Ding, K. Das, A.D. Clark Jr., P.L. Boyer, P. Lewi, P.A. Janssen, J.P. Kleim, M. Rosner, S.H. Hughes, and E. Arnold The Lys103Asn mutation of HIV-1 RT a novel mechanism of drug resistance J. Mol. Biol. 309 2001 437 445
26. H. Huang, R. Chopra, G.L. Verdine, and S.C. Harrison Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase implications for drug resistance Science 282 1998 1669 1675
27. A. Jacobo-Molina, J. Ding, R.G. Nanni, A.D. Clark Jr., X. Lu, C. Tantillo, R.L. Williams, G. Kamer, A.L. Ferris, and P. Clark 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 1993 6320 6324
28. P. Kellam, and B.A. Larder Recombinant virus assay a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates Antimicrob. Agents Chemother. 38 1994 23 30
29. L.A. Kohlstaedt, J. Wang, J.M. Friedman, P.A. Rice, and T.A. Steitz Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor Science 256 1992 1783 1790
30. J.P. Lalezari, K. Henry, M. O'Hearn, J.S. Montaner, P.J. Piliero, B. Trottier, S. Walmsley, C. Cohen, D.R. Kuritzkes, J.J. Eron Jr., J. Chung, R. DeMasi, L. Donatacci, C. Drobnes, J. Delehanty, and M. Salgo Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America N. Engl. J. Med. 13 2003 2175 2185
31. P.J. Lewi, M. de Jonge, F. Daeyaert, L. Koymans, M. Vinkers, J. Heeres, P.A.J. Janssen, E. Arnold, K. Das, A.D. Clark Jr., S.H. Hughes, P. Boyer, M.-P. de Béthune, R. Pauwels, K. Andries, M. Kukla, D. Ludovici, B. De Corte, R. Kavash, and C.Y. Ho On the detection of multiple-binding modes of ligands to proteins, from biological, structural, and modeling J. Comput.-Aided Mol. Des. 17 2003 129 134
32. J. Lindberg, S. Sigurdsson, S. Lowgren, H.O. Andersson, C. Sahlberg, R. Noreen, K. Fridborg, H. Zhang, and T. Unge Structural basis for the inhibitory efficacy of efavirenz (DMP-266), MSC194 and PNU142721 towards the HIV-1 RT K103N mutant Eur. J. Biochem. 269 2002 1670 1677
33. D.W. Ludovici, B.L. De Corte, M.J. Kukla, H. Ye, C.Y. Ho, M.A. Lichtenstein, R.W. Kavash, K. Andries, M. de Bethune, H. Azijn, R. Pauwels, P.J. Lewi, J. Heeres, L.M. Koymans, M.R. de Jonge, K.J. Van Aken, F.F. Daeyaert, K. Das, E. Arnold, and P.A. Janssen Evolution of anti-HIV drug candidates. Part 3 diarylpyrimidine (DAPY) analogues Bioorg. Med. Chem. Lett. 11 2001 2235 2239
34. D.W. Ludovici, R.W. Kavash, M.J. Kukla, C.Y. Ho, H. Ye, B.L. De Corte, K. Andries, M. de Bethune, H. Azijn, R. Pauwels, H.E. Moereels, J. Heeres, L.M. Koymans, M.R. de Jonge, K.J. Van Aken, F.F. Daeyaert, J.L. P, K. Das, E. Arnold, and P.A. Janssen Evolution of anti-HIV drug candidates. Part 2 diaryltriazine (DATA) analogues Bioorg. Med. Chem. Lett. 11 2001 2229 2234
35. D.W. Ludovici, M.J. Kukla, P.G. Grous, S. Krishnan, K. Andries, M. de Bethune, H. Azijn, R. Pauwels, E. De Clercq, E. Arnold, and P.A. Janssen Evolution of anti-HIV drug candidates. Part 1 From α - Anilinophenylacetamide (α -APA) to imidoyl thiourea (ITU) Bioorg. Med. Chem. Lett. 11 2001 2225 2228
36. H. Ohtaka, A. Velazquez-Campoy, D. Xie, and E. Freire Overcoming drug resistance in HIV-1 chemotherapy the binding thermodynamics of Amprenavir and TMC-126 to wild-type and drug-resistant mutants of the HIV-1 protease Protein Sci. 11 2002 1908 1916
37. W.C. Olson, and P.J. Maddon Resistance to HIV-1 entry inhibitors Curr. Drug Targets Infect. Disord. 3 2003 283 294
38. R. Pauwels, J. Balzarini, M. Baba, R. Snoeck, D. Schols, P. Herdewijn, J. Desmyter, and E. De Clercq Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds J. Virol. Methods 20 1988 309 321
39. R. Pauwels, K. Andries, J. Desmyter, D. Schols, M.J. Kukla, H.J. Breslin, A. Raeymaeckers, J. Van Gelder, R. Woestenborghs, and J. Heykants Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives Nature 343 1990 470 474
40. R. Pauwels, K. Andries, Z. Debyser, P. Van Daele, D. Schols, P. Stoffels, K. De Vreese, R. Woestenborghs, A.M. Vandamme, and C.G. Janssen 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 1993 1711 1715
41. R. Pauwels, K. Andries, Z. Debyser, M.J. Kukla, D. Schols, H.J. Breslin, R. Woestenborghs, J. Desmyter, M.A. Janssen, and E. De Clercq New tetrahydroimidazo[4,5,1 -jk][1,4]-benzodiazepin-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 1994 2863 2870
42. J. Ren, R. Esnouf, E. Garman, D. Somers, C. Ross, I. Kirby, J. Keeling, G. Darby, Y. Jones, and D. Stuart High resolution structures of HIV-1 RT from four RT-inhibitor complexes Nat. Struct. Biol. 2 1995 293 302
43. J. Ren, R. Esnouf, A. Hopkins, C. Ross, Y. Jones, D. Stammers, and D. Stuart The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO lessons for inhibitor design Structure 3 1995 915 926
44. J. Ren, R.M. Esnouf, A.L. Hopkins, J. Warren, J. Balzarini, D.I. Stuart, and D.K. Stammers Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives Biochemistry 37 1998 14394 14403
45. J. Ren, J. Diprose, J. Warren, R.M. Esnouf, L.E. Bird, S. Ikemizu, M. Slater, J. Milton, J. Balzarini, D.I. Stuart, and D.K. Stammers Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses J. Biol. Chem. 275 2000 5633 5639
46. J. Ren, J. Milton, K.L. Weaver, S.A. Short, D.I. Stuart, and D.K. Stammers Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase Struct. Fold Des. 8 2000 1089 1094
47. J. Ren, C.E. Nichols, P.P. Chamberlain, K.L. Weaver, S.A. Short, and D.K. Stammers Crystal structures of HIV-1 reverse transcriptases mutated at codons 100, 106 and 108 and mechanisms of resistance to non-nucleoside inhibitors J. Mol. Biol. 336 2004 569 578
48. K. Rittinger, G. Divita, and R.S. Goody Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors Proc. Natl. Acad. Sci. USA 92 1995 8046 8049
49. D.W. Rodgers, S.J. Gamblin, B.A. Harris, S. Ray, J.S. Culp, B. Hellmig, D.J. Woolf, C. Debouck, and S.C. Harrison The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1 Proc. Natl. Acad. Sci. USA 92 1995 1222 1226
50. M.N. Rousseau, L. Vergne, B. Montes, M. Peeters, J. Reynes, E. Delaporte, and M. Segondy Patterns of resistance mutations to antiretroviral drugs in extensively treated HIV-1-infected patients with failure of highly active antiretroviral therapy J. Acquir Immune. Defic. Syndr. 26 2001 36 43
51. S.U. Sankatsing, G.J. Weverling, M. Peeters, G. Van't Klooster, B. Gruzdev, A. Rakhmanova, S.A. Danner, S. Jurriaans, J.M. Prins, and J.M. Lange TMC125 exerts similar initial antiviral potency as a five-drug, triple class antiretroviral regimen AIDS 17 2003 2623 2627
52. S.G. Sarafianos, K. Das, J. Ding, P.L. Boyer, S.H. Hughes, and E. Arnold Touching the heart of HIV-1 drug resistance the fingers close down on the dNTP at the polymerase active site Chem. Biol. 6 1999 R137 R146
53. S.G. Sarafianos, K. Das, A.D. Clark Jr., J. Ding, P.L. Boyer, S.H. Hughes, and E. Arnold Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with β -branched amino acids Proc. Natl. Acad. Sci. USA 96 1999 10027 10032
54. S.G. Sarafianos, K. Das, C. Tantillo, A.D. Clark Jr., J. Ding, J.M. Whitcomb, P.L. Boyer, S.H. Hughes, and E. Arnold Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA DNA EMBO J. 20 2001 1449 1461
55. C.K. Shih, J.M. Rose, G.L. Hansen, J.C. Wu, A. Bacolla, and J.A. Griffin Chimeric human immunodeficiency virus type 1/type 2 reverse transcriptases display reversed sensitivity to nonnucleoside analog inhibitors Proc. Natl. Acad. Sci. USA 88 1991 9878 9882
56. R.A. Spence, W.M. Kati, K.S. Anderson, and K.A. Johnson Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors Science 267 1995 988 993
57. J. Stephenson The art of 'HAART' researchers probe the potential and limits of aggressive HIV treatments J. Am. Med. Assoc. 277 1997 614 616
58. C. Tantillo, J. Ding, A. Jacobo-Molina, R.G. Nanni, P.L. Boyer, S.H. Hughes, R. Pauwels, K. Andries, P.A. Janssen, and E. Arnold 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 1994 369 387
59. M. Udier-Blagovic, J. Tirado-Rives, and W.L. Jorgensen Validation of a model for the complex of HIV-1 reverse transcriptase with nonnucleoside inhibitor TMC125 J. Am. Chem. Soc. 125 2003 6016 6017
60. M. Udier-Blagovic, E.K. Watkins, J. Tirado-Rives, and W.L. Jorgensen Activity predictions for efavirenz analogues with the K103N mutant of HIV reverse transcriptase Bioorg. Med. Chem. Lett. 13 2003 3337 3340
61. Y. Van Herrewege, J. Michiels, J. Van Roey, K. Fransen, L. Kestens, J. Balzarini, P. Lewi, G. Vanham, and P. Janssen In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides Antimicrob. Agents Chemother. 48 2004 337 339
62. K. Van Vaerenbergh, T. Harrer, J.C. Schmit, A. Carbonez, E. Fontaine, M. Kurowski, M. Grunke, P. Low, A. Rascu, B. Schmidt, M. Schmitt, I. Thoelen, H. Walter, K. Van Laethem, M. Van Ranst, J. Desmyter, E. De Clercq, and A.M. Vandamme Initiation of HAART in drug-naive HIV type 1 patients prevents viral breakthrough for a median period of 35.5 months in 60% of the patients AIDS Res. Hum. Retroviruses 18 2002 419 426
63. J. Weber, J. Mesters, M. Lepsik, J. Prejdova, M. Svec, J. Sponarova, P. Mlcochova, K. Skalicka, K. Strisovsky, T. Uhlikova, M. Soucek, L. Machala, M. Stankova, J. Vondrasek, T. Klimkait, H. Kraeusslich, R. Hilgenfeld, and J. Konvalinka Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains J. Mol. Biol. 324 2002 739 754
64. X. Wei, S.K. Ghosh, M.E. Taylor, V.A. Johnson, E.A. Emini, P. Deutsch, J.D. Lifson, S. Bonhoeffer, M.A. Nowak, and B.H. Hahn Viral dynamics in human immunodeficiency virus type 1 infection Nature 373 1995 117 122