Insights on resistance to reverse transcriptase: The different patterns of interaction of the nucleoside reverse transcriptase inhibitors in the deoxyribonucleotide triphosphate binding site relative to the normal substrate

Journal of Medicinal Chemistry

Volumn 49, Issue 26, 2006, Pages 7675-7682

  Carvalho, Alexandra T P ^a   Fernandes, Pedro A ^a   Ramos, Maria J ^a  

^a UNIVERSITY OF PORTO   (Portugal)

Author keywords

[No Author keywords available]

Indexed keywords

2',3' DIDEHYDRO 2',3' DIDEOXYTHYMIDINE 5' TRIPHOSPHATE; 2',3' DIDEOXYCYTIDINE 5' TRIPHOSPHATE; DEOXYRIBONUCLEOTIDE; DEOXYRIBONUCLEOTIDE TRIPHOSPHATE; PHOSPHATE; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; STAVUDINE; UNCLASSIFIED DRUG; ZALCITABINE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ARTICLE; CATALYSIS; CRYSTAL STRUCTURE; DIPOLE; DRUG BINDING SITE; DRUG CONFORMATION; DRUG TREATMENT FAILURE; ENZYME SUBSTRATE COMPLEX; MOLECULAR DYNAMICS; MOLECULAR INTERACTION; PHOSPHORYLATION; SIMULATION; X RAY CRYSTALLOGRAPHY;

BINDING SITES; COMPUTER SIMULATION; DEOXYRIBONUCLEOTIDES; DRUG RESISTANCE, MULTIPLE, VIRAL; HIV; HIV-1 REVERSE TRANSCRIPTASE; HUMANS; MOLECULAR CONFORMATION; NUCLEOSIDES; POINT MUTATION; REVERSE TRANSCRIPTASE INHIBITORS; STAVUDINE; THYMINE NUCLEOTIDES; ZALCITABINE;

EID: 33845958917     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060698c     Document Type: Article

References (53)

1. Telesnitsky, A.; Goff, S. P. In Retroviruses; Coffin, J. M., Hughes, S. H., Varmus, H. E., Eds.; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 1997.
2. Bebenek, K.; Abbotts, J.; Roberts, J. D.; Wilson, S. H.; Kunkel, T. A. Specificity and mechanism of error-prone replication by human immunodeficiency virus-1 reverse transcriptase. J. Biol. Chem. 1989, 264, 16948-16956.
3. Coakley, E. P.; Gillis, J. M.; Hammer, S. M. Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine. AIDS 2000, 14, F9-F15.
4. Lin, P. F.; Gonzalez, C. J.; Griffith, B.; Friedland, G.; Calvez, V.; Ferchal, F.; Schinazi, R. F.; Shepp, D. H.; Ashraf, A. B.; Wainberg, M. A.; Soriano, V.; Mellors, J. W.; Colonno, R. J. Stavudine resistance: An update on susceptibility following prolonged therapy. Antiviral Ther. 1999, 4, 21-28.
5. Gu, Z.; Gao, Q.; Fang, H.; Salomon, H.; Parniak, M. A.; Goldberg, E.; Cameron, J.; Wainberg, M. A. Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2′,3′-dideoxycytidine and 2′,3′-dideoxy- 3′-thiacytidine. Antimicrob. Agents Chemother. 1994, 38, 275-281.
6. Zhang, D.; Caliendo, A. M.; Eron, J. J.; DeVore, K. M.; Kaplan, J. C.; Hirsch, M. S.; D'Aquila, R. T. Resistance to 2′,3′-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 1994, 38, 282-287.
7. St. Clair, M. H.; Martin, J. L.; Tudor-Williams, G.; Bach, M. C.; Vavro, C. L.; King, D. M.; Kellam, P.; Kemp, S. D.; Larder, B. A. Resistance to dd1 and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991, 253, 1557-1559.
8. Gao, Q.; Gu, Z.; Parniak, M. A.; Cameron, J.; Cammack, N.; Boucher, C.; Wainberg, M. A. The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2′,3′-dideoxy-3′-thiacytidine. Antimicrob. Agents Chemother. 1993, 37, 1390-1392.
9. Schinazi, R. F.; Lloyd, R. M., Jr.; Nguyen, M. H.; Cannon, D. L.; McMillan, A.; Ilksoy, N.; Chu, C. K.; Liotta, D. C.; Bazmi, H. Z.; Mellors, J. W. Antiviral drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase occur in specific RNA structural regions. Antimicrob. Agents Chemother. 1993, 37, 875-881.
10. Tisdale, M.; Kemp, S. D.; Parry, N. R., Larder, B. A. 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. U.S.A. 1993, 90, 5653-5656.
11. Carvalho, A. P.; Fernandes, P. A.; Ramos, M. J. Molecular insights into the mechanisms of HIV-1 reverse transcriptase resistance to nucleoside analogues. Mini.-Rev. Med. Chem. 2006, 6, 549-555.
12. Balzarini, J. Suppression of resistance to drugs targeted to human immunodeficiency virus reverse transcriptase by combination therapy Biochem. Pharm. 1999, 58, 1.
13. Selmi, B.; Boretto, J.; Navarro, J. M.; Sire, J.; Longhi, S.; Guerreiro, C.; Mulard, L.; Sarfati, S.; Canard, B. The valine-to-threonine 75 substitution in human immunodeficiency virus type 1 reverse transcriptase and its relation with stavudine resistance. J. Mol. Biol. 2001, 276, 13965-13974.
14. Selmi, B.; Boretto, J.; Sarfati, S. R.; Guerreiro, C.; Canard, B. Mechanism-based suppression of dideoxynucleotide resistance by K65R human immunodeficiency virus reverse transcriptase using an alpha-boranophosphate nucleoside analogue. J. Biol. Chem. 2001, 276, 48466-48472.
15. Sluis-Cremer, N.; Arion, D.; Parniak, M.A. Molecular mechanisms of HIV-1 resistance to nucleoside reverse transcriptase inhibitors (NRTIs). Cell. Mol. Life Scil. 2000, 57, 1408-1422.
16. Arion, D.; Kaushik, N.; McCormick, S.; Borkow, G.; Parniak, M. A. Phenotypic mechanism 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, 15908-15917.
17. Meyer, P. R.; Matsura, S. E.; Mian, A. M.; So, A. G.; Scott, W. A. A mechanism of AZT resistance: An increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol. Cell 1999, 4, 35-43.
18. Naeger, L.; Margot, N.; Miller, M. ATP-dependent removal of nucleoside reverse transcriptase inhibitors by human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemoter. 2002, 46, 2179-2184.
19. Boyer, P. L.; Sarafianos, S. G.; Arnold, E.; Hughes, S. H. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J. Virol. 2001, 75, 4832-4842.
20. Boyer, P. L.; Sarafianos, S. G.; Arnold, E.; Hughes, S. H. 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, 9143-9151.
21. Boyer, P. L.; Sarafianos, S. G.; Arnold, E.; Hughes, S. H. 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, 3248-3256.
22. Mas, A.; Parera, M.; Briones, C.; Soriano, V.; Martinez, M. A.; Domingo, E.; Menedez-Arias, L. Role of a dipeptide insertion between codons 69 and 70 of HIV-1 reverse transcriptase in the mechanism of AZT resistance. EMBO J. 2000, 19, 5752-5761.
23. Meyer, P. R.; Matsuura, S. E.; So, A. G.; Scott, W. A. Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 13471-13476.
24. Meyer, P. R.; Matsuura, S. E.; Schinazi, R. F.; So, A. G.; Scott, W. A. 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 Chem. 2000, 44, 3465-3472.
25. Meyer, P. R.; Lennestrand, J.; Matsuura, S. E.; Larder, B. A.; Scott, W. A. Relationship between 3′-azido-3′-deoxythymidine resistance and primer unblocking activity in foscarnet-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase. J. Virol. 2003, 77, 6127-6137.
26. Arion, D.; Sluis-Cremer, N.; Parniak, M. A. Mechanism by which phosphonoformic acid resistance mutations restore 3′-azido-3′- deoxythymidine (AZT) sensitivity to AZT-resistant HIV-1 reverse transcriptase. J. Biol. Chem. 2000, 275, 9251-9255.
27. Götte, M.; Arion, D.; Parniak, M. A.; Wainberg, M. A. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. J. Virol. 2000, 74, 3579-3585.
28. Krebs, R.; Immendorfer, U.; Thrall, S. H.; Wohrl, B. M.; Goody, R. S. Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. Biochemistry 1997, 36, 10292-10300.
29. Martin, J. L.; Wilson, J. E.; Haynes, R. L.; Furman, P. A. Mechanism of resistance of human immunodeficiency virus type 1 to 2′,3′- dideoxyinosine. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6135-6139.
30. Gu, Z.; Quan, Y.; Li, Z.; Arts, E. J.; Wainberg, M. A. Effects of non-nucleoside inhibitors of human immunodeficiency virus type 1 in cell-free recombinant reverse transcriptase assays. J. Biol. Chem. 1995, 270, 31046-31051.
31. Isel, C.; Ehresmann, C.; Walter, P.; Ehresmann, B.; Marquet, R. The emergence of different resistance mechanisms toward nucleoside inhibitors is explained by the properties of the wild type HIV-1 reverse transcriptase. J. Biol. Chem. 2001, 276, 48725-48732.
32. Huang, H.; Chopra, R.; Verdine, G. L.; Harrison, S. C. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: Implications for drug resistance. Science 1998, 282, 1669-1675.
33. Jamburuthugoda, V. K.; Guo, D.; Wedekind, J. E.; Kim, B. Kinetic evidence for interaction of human immunodeficiency virus type 1 reverse transcriptase with the 3′-OH of the incoming dTTP substrate. Biochemistry 2005, 44, 10635-10643.
34. Shirasaka, T.; Klavlick, M. F.; Ueno, T.; et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc. Natl. Acad. Sci U.S.A. 1995, 92, 2398-2402.
35. Iversen, A. K.; Shafer, R. W.; Werly, K.; Winters, M. A.; Mullins, J. L.; Chesebro, B.; Merigan, T. C. Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy. J. Virol. 1996, 70, 1086-1090.
36. Kavlick, M. F.; Wyvill, K.; Yarchoan, R.; Mitsuya, H. Emergence of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 variants, viral sequence variation, and disease progression in patients receiving antiretroviral chemotherapy. J. Inf. Dis. 1998, 177, 1506-1513.
37. Ueno, T.; Shirasaka, T.; Mitsuya, H. Enzymatic characterization of human immunodeficiency virus type 1 reverse transcriptase resistant to multiple 2′,3′-dideoxynucleoside 5′-triphosphates. J. Biol. Chem. 1995, 270, 23605-23611.
38. Garcia Lerma, J.; Schinazi, R. F.; Juodawlkis, A. S.; Soriano, V.; Lin, Y.; Tatti, K.; Rimland, D.; Folks, T. M.; Heneine, W. A rapid non-culture-based assay for clinical monitoring of phenotypic resistance of human immunodeficiency virus type 1 to lamivudine (3TC). Antimicrob. Agents Chemother. 1999, 43, 264-270.
39. Roge, B. T.; Katezenstein, T. L.; Obel, N.; et al. K65R with and without S68: A new resistance profile in vivo detected in most patients failing abacavir, didanosine and stavudine. Antivir. Ther. 2003, 8, 173.
40. Schinazi, R. F.; Larder, B. A.; Mellors, J. W. Mutations in retroviral genes associated with drug resistance. Int. Antivir. News 1996, 4, 95-107.
41. Boyer, P. L.; Ferris, A. L.; Hughes, S. H. Mutational analysis of the fingers domain of human immunodeficiency virus type 1 reverse transcriptase. J. Virol. 1992, 66, 7533-7537.
42. Kim, B.; Hathaway, T. R.; Loeb, L. A. Human immunodeficiency virus reverse transcriptase. Functional mutants obtained by random mutagenesis coupled with genetic selection in Escherichia coli. J. Biol. Chem. 1996, 271, 4872-4878.
43. Vaccaro, J. A.; Parnell, K. M.; Terezakis, S. A.; Anderson, K. S. Mechanism of inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: An equivalent incorporation efficiency relative to the natural substrate dTTP. Antimicrob. Agents Chemother. 2000, 44, 217-221.
44. Kerr, S. G.; Anderson, K. S. Pre-steady-state kinetic characterization of wild type and 3′-azido-3′-deoxythymidine (AZT) resistant human immunodeficiency virus type 1 reverse transcriptase: Implication of RNA directed DNA polymerization in the mechanism of AZT resistance. Biochemistry 1997, 36, 14064-14070.
45. Feng, J. Y.; Anderson, K. S. Insights into the molecular mechanism of mitochondrial toxicity by AIDS drugs. Biochemistry 1999, 38, 55-63.
46. Rigourd, M.; Lanchy, J. M.; Le Grice, S. F.; Ehresmann, B.; Ehresmann, C.; Marquet, R. Inhibition of the initiation of HIV-1 reverse transcription by 3′-azido-3′-deoxythymidine. Comparison with elongation. J. Biol. Chem. 2000, 275, 26944-26951.
47. Carvalho, A. T. P.; Fernandes, P.A.; Ramos, M. J. Molecular dynamics model of unliganded HIV-1 reverse transcriptase. Med. Chem. J., in press.
48. Case, D. A.; Darden, T. A.; Cheatham, T. E.; Simmerling, C. L., III; Wang, J.; Duke, R. E.; Luo, R.; Merz, K. M.; Wang, B.; Pearlman, D. A.; Crowley, M.; Brozell, S.; Tsui, V.; Gohlke, H.; Mongan, J.; Hornak, V.; Cui, G.; Beroza, P.; Schafmeiste, R. C.; Caldwell, J. W.; Ross, W. S.; Kollman, P. A. AMBER 8; University of California: San Francisco, 2004.
49. Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M. Jr.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W.; Kollman, P. A. A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules. J. Am. Chem. Soc. 1995, 117, 5179-5197.
50. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, revision B.04; Gaussian, Inc.: Wallingford, CT, 2004.
51. Cammi, R.; Mennucci, B.; Tomasi, J. Fast evaluation of geometries and properties of excited molecules in solution: A Tamm-Dancoff model with application to 4-dimethylaminobenzonitrile. J. Phys. Chem. A. 2000, 104, 5631-5637.
52. Singh, U. C.; Kollman, P. A. An approach to computing electrostatic charges for molecules. J. Comput. Chem. 1984, 5, 129-145.
53. Bester, B. H.; Merz, K. H.; Kollman, P. A. Atomic charges derived from semiempirical methods. J. Comput. Chem. 1990, 11, 431-439.