Selective targeting of the HIV-1 reverse transcriptase catalytic complex through interaction with the "primer grip" region by pyrrolobenzoxazepinone non-nucleoside inhibitors correlates with increased activity towards drug-resistant mutants

Biochemical Pharmacology

Volumn 76, Issue 2, 2008, Pages 156-168

  Zanoli, Samantha ^a   Gemma, Sandra ^b   Butini, Stefania ^b   Brindisi, Margherita ^b   Joshi, Bhupendra P ^b   Campiani, Giuseppe ^b   Fattorusso, Caterina ^b,c   Persico, Marco ^b,c   Crespan, Emmanuele ^a   Cancio, Reynel ^a   Spadari, Silvio ^a   Hübscher, Ulrich ^d   Maga, Giovanni ^a,b  

^a CNR   (Italy)

^b UNIVERSITY OF SIENA   (Italy)

^c UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^d UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

Drug resistant; HIV 1; Kinetics; Molecular modeling; NNRTIs; Reverse transcriptase

Indexed keywords

ANTIGEN P24; EFAVIRENZ; NEVIRAPINE; PBO 335; PBO 427; PBO 431; PBO 437; PBO 442; PBO 461; PYRROLOBENZOXAZEPINONE DERIVATIVE; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR;

ANIMAL CELL; ANTIVIRAL ACTIVITY; ARTICLE; CALCULATION; CATALYSIS; CD4+ T LYMPHOCYTE; COMPLEX FORMATION; CONTROLLED STUDY; CORRELATION ANALYSIS; CROSS RESISTANCE; CYTOTOXICITY; DISSOCIATION; DRUG CONFORMATION; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME KINETICS; ENZYME PURIFICATION; ENZYME SUBSTRATE; GENE MUTATION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; KINETICS; MOLECULAR DOCKING; MOLECULAR MODEL; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; VIRUS MUTANT; WILD TYPE;

3T3 CELLS; ANIMALS; AZEPINES; BENZOXAZINES; CATALYSIS; CELL LINE; CELLS, CULTURED; DNA-DIRECTED DNA POLYMERASE; DRUG RESISTANCE, VIRAL; HIV REVERSE TRANSCRIPTASE; HIV-1; HUMANS; LEUKOCYTES, MONONUCLEAR; MICE; MODELS, MOLECULAR; MUTATION; NEVIRAPINE; REVERSE TRANSCRIPTASE INHIBITORS;

EID: 45649084429     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bcp.2008.04.009     Document Type: Article

References (16)

1. De Clercq E. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future. Chem Biodivers 1 (2004) 44-64
2. Balzarini J. Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Curr Top Med Chem 4 (2004) 921-944
3. Rivero A., Mira J.A., and Pineda J.A. Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 59 (2007) 342-346
4. Vella S., and Palmisano L. Antiretroviral therapy: state of the HAART. Antivir Res 45 (2000) 1-7
5. Richman D., Shih C.-K., Lowy I., Rose J., Prodanovich P., Goff S., et al. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci USA 88 (1991) 11241-11245
6. Boone L.R. Next-generation HIV-1 non-nucleoside reverse transcriptase inhibitors. Curr Opin Invest Drugs 7 (2006) 128-135
7. Zhou Z., Lin X., and Madura J.D. HIV-1 RT nonnucleoside inhibitors and their interaction with RT for antiviral drug development. Infect Disord Drug Targets 6 (2006) 391-413
8. Campiani G., Morelli E., Fabbrini M., Nacci V., Greco G., Novellino E., et al. Pyrrolobenzoxazepinone derivatives as non-nucleoside HIV-1 RT inhibitors: further structure-activity relationship studies and identification of more potent broad-spectrum HIV-1 RT inhibitors with antiviral activity. J Med Chem 42 (1999) 4462-4470
9. Locatelli G.A., Campiani G., Cancio R., Morelli E., Ramunno A., Gemma S., et al. Effects of drug resistance mutations L100I and V106A on the binding of pyrrolobenzoxazepinone nonnucleoside inhibitors to the human immunodeficiency virus type 1 reverse transcriptase catalytic complex. Antimicrob Agents Chemother 48 (2004) 1570-1580
10. Fattorusso C., Gemma S., Butini S., Huleatt P., Catalanotti B., Persico M., et al. Specific targeting highly conserved residues in the HIV-1 reverse transcriptase primer grip region. Design, synthesis, and biological evaluation of novel, potent, and broad spectrum NNRTIs with antiviral activity. J Med Chem 48 (2005) 7153-7165
11. Pelemans H., Esnouf R., De Clerq E., and Balzarini J. Mutational analysis of Trp-229 of human immunodeficiency virus type 1 reverse transcriptase (RT) identifies this amino acid residue as a prime target for the rational design of new non-nucleoside RT inhibitors. Mol Pharmacol 57 (2000) 954-960
12. Wohrl B.M., Krebs R., Thrall S.H., Le Grice S.F., Scheidig A.J., and Goody R.S. Kinetic analysis of four HIV-1 reverse transcriptase enzymes mutated in the primer grip region of p66 implications for DNA synthesis and dimerization. J Biol Chem 272 (1997) 17581-17587
13. Boyer P.L., Ferris A.L., Clark P., Whitmer J., Frank P., Tantillo C., et al. Mutational analysis of the fingers and palm subdomains of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase. J Mol Biol 243 (1994) 472-483
14. Maga G., Amacker M., Ruel N., Hubscher U., and Spadari S. Resistance to nevirapine of HIV-1 reverse transcriptase mutants: loss of stabilizing interactions and thermodynamic or steric barriers are induced by different single amino acid substitutions. J Mol Biol 274 (1997) 738-747
15. Maga G., Ubiali D., Salvetti R., Pregnolato M., and Spadari S. Selective interaction of the human immunodeficiency virus type 1 reverse transcriptase nonnucleoside inhibitor efavirenz and its thio-substituted analog with different enzyme-substrate complexes. Antimicrob Agents Chemother 44 (2000) 1186-1194
16. Huang H., Chopra R., Verdine G.L., and Harrison S.C. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282 (1998) 1669-1675