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Chapter 3 : Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors

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Abstract:

This chapter discusses the non-nucleoside reverse transcriptase inhibitors (NNRTI), which is a valuable component of first-line highly active antiretroviral therapy (HAART) today. Reverse transcriptase (RT) is an essential enzyme in the replication cycle of HIV. Several high-resolution structures representing the different intermediates in the polymerization reaction are available for human immunodeficiency virus type 1 (HIV-1) RT. Rilpivirine is currently in phase IIb clinical trials for treatment of HIV-1 infection in treatment-naïve subjects. With the widespread use of anti-HIV therapy, resistance has grown steadily and is now common among treatment-experienced HIV-infected patients, with NNRTI resistance occurring in 20 to 30% of patients. This has changed with the DUET-1 and DUET-2 trials, two large phase III clinical trials that examined the efficacy of etravirine in treatment-resistant HIV-1-infected patients. K103N and Y181C were the first NNRTI mutations to be identified and to date are among the most prevalent in clinical HIV-1 isolates. They have been observed in patients failing on nevirapine, efavirenz, or delavirdine, and the clinical utility of these drugs is hampered by the presence of a single K103N or Y181C mutation. Recently, predictors of virologic response to etravirine were identified based on pooled data from DUET-1 and DUET-2.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figures

Image of Figure 1.
Figure 1.

The reverse transcription process. Reverse transcription starts from a tRNA primer hybridized to the primer binding site (PBS) on the single-stranded HIV RNA genome. For synthesis of the proviral DNA, the enzyme not only needs DNA polymerase activity but also performs a strand transfer, which is facilitated by repeat sequences (R) at both ends of the genome. In addition, the RNA strand must be degraded to allow second DNA strand synthesis; the required RNase H activity is also embedded in the RT enzyme. Because some parts of the RNA sequence are less susceptible to RNase H activity, remaining RNA fragments (e.g., polypurine track sequence [PPT]) may act as primers for second DNA strand synthesis.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Image of Figure 2.
Figure 2.

Conformational changes of HIV-1 RT observed upon binding of p/t, dNTP, and non-nucleoside RT inhibitors. HIV-1 RT consists of a p66 subunit with thumb and fingers domain and a p51 subunit that supports the conformation of p66. For polymerization the thumb opens allowing p/t binding followed by a turning of the fingers upon dNTP binding. This ensures correct positioning of the primer end towards the dNTP and allows its incorporation (left). NNRTIs can bind the unliganded RT as well as the liganded RT. The structure of HIV-1 RT and NNRTIs in the presence of p/t and dNTP has not yet been resolved (boxed figures). NNRTI binding occurs in an induced pocket on the p66/p51 dimer interface. This causes different structural changes: the thumb moves in an extreme upward position, the primer grip repositions, and the dNTP binding site changes (arrows). The resulting repositioning of the primer end relative to the dNTP makes polymerization impossible.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Image of Figure 3.
Figure 3.

First NNRTI.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Image of Figure 4.
Figure 4.

NNRTIs currently approved for clinical use.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Image of Figure 5.
Figure 5.

From TIBO to ITU.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Image of Figure 6.
Figure 6.

Oxidative instability of the ITU series.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figure 7.

Serendipitous synthesis of the first DATA compound, obtained in an effort to stabilize the ITUs.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Image of Figure 8.
Figure 8.

From DATA to etravirine (TMC125).

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figure 9.

The discovery of the arylpyridone class.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figure 10.

Identification of rilpivirine (TMC278).

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figure 11.

First steps in the benzophenone class.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Image of Figure 12.
Figure 12.

Optimizations of the benzophenone class.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figure 13.

Optimization in the triazole class.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figure 14.

Indole class evolution.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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Figure 15.

From nevirapine to BILR-355 BS.

Citation: Jochmans D, Vingerhoets J, Arnoult E, Geeraert L, Guillemont J. 2009. Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors, p 33-50. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch3
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