HIV-1 Reverse Transcriptase Still Remains a New Drug Target: Structure, Function, Classical Inhibitors, and New Inhibitors with Innovative Mechanisms of Actions

Overview

Journal Mol Biol Int

Publisher Hindawi

Specialty Molecular Biology

Date 2012 Jul 11

PMID 22778958

Citations 47

Authors

Francesca Esposito

Angela Corona

Enzo Tramontano

Affiliations

Soon will be listed here.

Abstract

During the retrotranscription process, characteristic of all retroviruses, the viral ssRNA genome is converted into integration-competent dsDNA. This process is accomplished by the virus-coded reverse transcriptase (RT) protein, which is a primary target in the current treatments for HIV-1 infection. In particular, in the approved therapeutic regimens two classes of drugs target RT, namely, nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). Both classes inhibit the RT-associated polymerase activity: the NRTIs compete with the natural dNTP substrate and act as chain terminators, while the NNRTIs bind to an allosteric pocket and inhibit polymerization noncompetitively. In addition to these two classes, other RT inhibitors (RTIs) that target RT by distinct mechanisms have been identified and are currently under development. These include translocation-defective RTIs, delayed chain terminators RTIs, lethal mutagenesis RTIs, dinucleotide tetraphosphates, nucleotide-competing RTIs, pyrophosphate analogs, RT-associated RNase H function inhibitors, and dual activities inhibitors. This paper describes the HIV-1 RT function and molecular structure, illustrates the currently approved RTIs, and focuses on the mechanisms of action of the newer classes of RTIs.

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References

Felts A, Labarge K, Bauman J, Patel D, Himmel D, Arnold E . Identification of alternative binding sites for inhibitors of HIV-1 ribonuclease H through comparative analysis of virtual enrichment studies. J Chem Inf Model. 2011; 51(8):1986-98. PMC: 3159817. DOI: 10.1021/ci200194w. View

Esposito F, Kharlamova T, Distinto S, Zinzula L, Cheng Y, Dutschman G . Alizarine derivatives as new dual inhibitors of the HIV-1 reverse transcriptase-associated DNA polymerase and RNase H activities effective also on the RNase H activity of non-nucleoside resistant reverse transcriptases. FEBS J. 2011; 278(9):1444-57. PMC: 3682423. DOI: 10.1111/j.1742-4658.2011.08057.x. View

Billamboz M, Bailly F, Lion C, Touati N, Vezin H, Calmels C . Magnesium chelating 2-hydroxyisoquinoline-1,3(2H,4H)-diones, as inhibitors of HIV-1 integrase and/or the HIV-1 reverse transcriptase ribonuclease H domain: discovery of a novel selective inhibitor of the ribonuclease H function. J Med Chem. 2011; 54(6):1812-24. DOI: 10.1021/jm1014692. View

Skillman A, Maurer K, Roe D, Stauber M, Eargle D, Ewing T . A novel mechanism for inhibition of HIV-1 reverse transcriptase. Bioorg Chem. 2003; 30(6):443-58. DOI: 10.1016/s0045-2068(02)00502-3. View

Chung S, Wendeler M, Rausch J, Beilhartz G, Gotte M, OKeefe B . Structure-activity analysis of vinylogous urea inhibitors of human immunodeficiency virus-encoded ribonuclease H. Antimicrob Agents Chemother. 2010; 54(9):3913-21. PMC: 2935023. DOI: 10.1128/AAC.00434-10. View

Cox S, Southby J . Apricitabine--a novel nucleoside reverse transcriptase inhibitor for the treatment of HIV infection that is refractory to existing drugs. Expert Opin Investig Drugs. 2009; 18(2):199-209. DOI: 10.1517/13543780802641337. View

Zhang Z, Walker M, Xu W, Shim J, Girardet J, Hamatake R . Novel nonnucleoside inhibitors that select nucleoside inhibitor resistance mutations in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 2006; 50(8):2772-81. PMC: 1538665. DOI: 10.1128/AAC.00127-06. View

McDowell J, Chittick G, Stevens C, Edwards K, Stein D . Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2000; 44(6):1686-90. PMC: 89933. DOI: 10.1128/AAC.44.6.1686-1690.2000. View

Grohmann D, Godet J, Mely Y, Darlix J, Restle T . HIV-1 nucleocapsid traps reverse transcriptase on nucleic acid substrates. Biochemistry. 2008; 47(46):12230-40. DOI: 10.1021/bi801386r. View

10.

Schinazi R, Lloyd Jr R, Nguyen M, Cannon D, McMillan A, Ilksoy N . Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993; 37(4):875-81. PMC: 187791. DOI: 10.1128/AAC.37.4.875. View

11.

Dutschman G, Bridges E, Liu S, Gullen E, Guo X, Kukhanova M . Metabolism of 2',3'-dideoxy-2',3'-didehydro-beta-L(-)-5-fluorocytidine and its activity in combination with clinically approved anti-human immunodeficiency virus beta-D(+) nucleoside analogs in vitro. Antimicrob Agents Chemother. 1998; 42(7):1799-804. PMC: 105686. DOI: 10.1128/AAC.42.7.1799. View

12.

De Clercq E . Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Farmaco. 1999; 54(1-2):26-45. DOI: 10.1016/s0014-827x(98)00103-7. View

13.

Camarasa M, Velazquez S, San-Felix A, Perez-Perez M, Gago F . Dimerization inhibitors of HIV-1 reverse transcriptase, protease and integrase: a single mode of inhibition for the three HIV enzymes?. Antiviral Res. 2006; 71(2-3):260-7. DOI: 10.1016/j.antiviral.2006.05.021. View

14.

Sohl C, Singh K, Kasiviswanathan R, Copeland W, Mitsuya H, Sarafianos S . Mechanism of interaction of human mitochondrial DNA polymerase γ with the novel nucleoside reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine indicates a low potential for host toxicity. Antimicrob Agents Chemother. 2011; 56(3):1630-4. PMC: 3294915. DOI: 10.1128/AAC.05729-11. View

15.

Tang J, Maddali K, Dreis C, Sham Y, Vince R, Pommier Y . N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase. ACS Med Chem Lett. 2011; 2(1):63-67. PMC: 3074239. DOI: 10.1021/ml1002162. View

16.

Sluis-Cremer N, Tachedjian G . Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res. 2008; 134(1-2):147-56. PMC: 2745993. DOI: 10.1016/j.virusres.2008.01.002. View

17.

Arion D, Sluis-Cremer N, Min K, Abram M, Fletcher R, Parniak M . Mutational analysis of Tyr-501 of HIV-1 reverse transcriptase. Effects on ribonuclease H activity and inhibition of this activity by N-acylhydrazones. J Biol Chem. 2001; 277(2):1370-4. DOI: 10.1074/jbc.M110254200. View

18.

Zhan P, Chen X, Li D, Fang Z, De Clercq E, Liu X . HIV-1 NNRTIs: structural diversity, pharmacophore similarity, and implications for drug design. Med Res Rev. 2011; 33 Suppl 1:E1-72. DOI: 10.1002/med.20241. View

19.

Rausch J, Le Grice S . 'Binding, bending and bonding': polypurine tract-primed initiation of plus-strand DNA synthesis in human immunodeficiency virus. Int J Biochem Cell Biol. 2004; 36(9):1752-66. DOI: 10.1016/j.biocel.2004.02.016. View

20.

Esnouf R, Ren J, Hopkins A, Ross C, Jones E, Stammers D . 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 U S A. 1997; 94(8):3984-9. PMC: 20554. DOI: 10.1073/pnas.94.8.3984. View