Nonnucleoside inhibitors

Nonnucleoside Inhibitors Nevirapine and efavirenz are active inhibitors of reverse transcriptase, that is, they do not require phosphorylation. Adverse reactions include rashes and interactions involving cytochrome P450 isozymes (CYP). 

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Kleim JP, ROsner M, Winkler I, Paessens A, Kirsch R, Hsiou Y, Arnolds E, Riess G (1996) Selective pressure of a quinoxaline nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on HIV-1 replication results in the emergence of nucleoside RT-inhibitor-specific (RT Leu-74 -> Val or He and Val-75 - > Leu or He) HIV-1 mutants, Proc Natl Acad Sci USA 93 34-38... 

Richman D, Shih C-K, Lowy I, Rose J, Prodanovich P, Goff S, Griffin J. Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture. Proc Natl Acad Sci USA 1991 88 11241-11245. 

Schlabach AJ, Wolfgang JA, Condra JH. Functional analysis of HIV-1 reverse transcriptase amino acids involved in resistance to multiple nonnucleoside inhibitors. J Biol Chem 1992 267 17526-17530. 

Byrnes VW, Sardana W, Schleif WA, Condra JH, Waterbury JA, Wolfgang JA, Long WJ, Schneider CL, Schlabach AJ, Wolanski BS, Graham DJ, Gotlib L, Rhodes A, Titus DL, Roth E, Blahy OM, Quintero JC, Staszewski S, Emini EA. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother 1993 37 1576-1579. 

Balzarini J, Karlsson A, Vandamme A-M, Perez-Perez M-J, Zhang H, Vrang L, Oberg B, Backbro K, Unge T, San-Felix A, Velazquez S, Camarasa M-J, De Clercq E. Human immunodeficiency virus type 1 (HIV-1) strains selected for resistance against the HIV-l-specific [2, 5 -bis-0-(rert-butyldi-methylsilyl)-3 -spiro-5"-(4"-amino-1", 2"-oxathiole-2", 2"-dioxide)]-fi-D-pen-tofuranosyl (TSAO) nucleoside analogues retain sensitivity to HIV-l-specific nonnucleoside inhibitors. Proc Natl Acad Sci USA 1993 90 6952-6956. 

E. Arnold, Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors, Nature Struct. Biol. 2 407 (1995). 

Pyrrolopyridines substituted at the 2-position of dipyridodiazepinones have been prepared for study as nonnucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase <1997JME2430>. Compound 141, synthesized from pyrrolo[2,3-, ]pyridine as a starting material, has emerged as a novel inhibitor of HIV-1. Compound 141 acts by interfering with the initial viral entry process <2003JME4236>. 

Biswal, . K., Wang, M., Cherney, M. M., Chan, L., Yannopoulos, C. G., Bilimoria, D., Bedard, J., James, M. N. (2006) Nonnucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition. /Mol Biol 361, 33-45. 

Boyer PL, Ding J, Arnold E, Hughes SH. Drug resistance of human immunodeficiency virus type 1 reverse transcriptase subunit specificity of mutations that confer resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother 1994 38 1909-1914. 

Spence RA, Kati WM, Anderson KS, Johnson KA. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 1995 267 988-993. 

Rittinger K, Divita G, Goody R. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc Natl Acad Sci USA 1995 92 8046-8049. 

Smith MBK, Rouzer CA, Taneyhill LA, Smith NA, Hughes SH, Boyer PL, et al. Molecular modeling studies of HIV-1 reverse transcriptase nonnucleoside inhibitors Total energy of complexation as a predictor of drug placement and activity. Protein Science 1995 4 2203-2222. 

Dueweke TJ, Pushkarskaya T, Poppe SM, Swaney SM, Zhao JQ, Chen ISY, et al. A mutation in reverse transcriptase of bis(heteroaryl) piperazine-resistant human immunodeficiency vims type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc Natl Acad Sci USA 1993 90 4713 1717. 

Young SD, Britcher SF, Tran LO, Payne LS, et al. 1995. Erfavirenz A novel highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimi-crog Agents Chemother. 39 2602-2605. 

Fujihashi T, Hara H, Sakata T, Mori K, Higuchi H, Tanaka A, Kaji H, Kaji A (1995) Anti-Human Immunodeficiency Virus (HIV) Activities of Halogenated Gomisin J Derivatives, New Nonnucleoside Inhibitors of HIV Type 1 Reverse Transcriptase. Antimicrob Agents Chemother 39 2000... 

Pata, J. D., Stirtan, W. G., Goldstein, S. W., and Steitz, T. A. (2004). Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors. Proc. Natl. Acad. Sri. USA 101, 10548-10553. 

Smerdon, S. J., Jager, J., Wang, J., Kohlstaedt, L. A., Chirino, A.J., Friedman, J. M., Rice, P. A., and Steitz, T. A. (1994). Structure of the binding site for nonnucleoside inhibitors of the reverse transcriptase of human immunodeficiency virus type 1. Proc. Natl. Acad. Sd. USA91, 3911-3915. 

Zhou, Z., Madura, J.D. 3D QSAR Analysis of HIV-1 RT Nonnucleoside Inhibitors, TIBO Derivatives Based on Docking Conformation and Alignment. /. Chem. Inf Comput. Sci. 2004, 44, 2167-2178. 

In general, DNA methyltransferase in inhibitors can be divided into two subgroups nucleoside and nonnucleoside inhibitors. The first group consists of decitabine (1), azacitidine (2), and zebularine (3). These three inhibitors were directly compared in four... 

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