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Chapter 4 : Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase
Authors:
Jérôme Deval1,
Matthias Götte2
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Affiliations:
1: Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304;
2: Department of Microbiology & Immunology, McGill University, Montreal, Quebec, Canada
Content Type: Monograph
Publication Year:
2009
Category: Viruses and Viral Pathogenesis; Clinical Microbiology
Book DOI:
10.1128/9781555815493
Chapter DOI:
10.1128/9781555815493.ch4
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Abstract:
More than 20 different antiretroviral agents have been approved for human immunodeficiency virus (HIV) treatment. These compounds target distinct stages in the life cycle of this retrovirus that include (i) its entry into the cytoplasm, which marks the beginning of the infection; (ii) the process of reverse transcription, i.e., the conversion of the single-stranded RNA genome into double-stranded DNA; (iii) the integration of proviral, double-stranded DNA into the host chromosome; and (iv) the processing of viral precursor proteins at later stages. These steps are vital for viral replication, and with the exception of the entry process, each of the aforementioned reactions involves viral enzymes, i.e., the reverse transcriptase (RT), the integrase, and the protease, respectively, that can be targeted by antiretroviral drugs. This chapter focuses on nucleoside analogue RT inhibitors (NRTIs) in the context of mechanisms of action and resistance and on the implications for the development of future strategies designed to counteract resistance. All approved NRTIs show a broad spectrum of antiviral activity against HIV-1, HIV- 2, and sometimes even hepatitis B virus (HBV), which points to structurally highly related active sites. A given mutation or mutational cluster can affect susceptibility to different NRTIs to various degrees, which makes it difficult to group the mutations. It will be interesting to investigate how established and novel NRTIs can be most effectively combined with new classes of compounds with the ultimate goal of further reducing the risk of resistance development, while maintaining high standards regarding problems associated with toxicities and dosing.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
Figures
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase
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Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig01
Figure 1.
Crystal structure of HIV-1 RT. (A) Ribbon representation of the apoenzyme. Subdomains of p66 are labeled. (B) Molecular surface of HIV-1 RT, with the same orientation as in panel A. (C) Binary complex of the enzyme with its polynucleotide substrate. The distance between the active site of the polymerase domain and the RNase H domain is shown by arrows.
10.1128/9781555815493/f0052-01_thmb.gif
10.1128/9781555815493/f0052-01.gif
Figure 1.
Crystal structure of HIV-1 RT. (A) Ribbon representation of the apoenzyme. Subdomains of p66 are labeled. (B) Molecular surface of HIV-1 RT, with the same orientation as in panel A. (C) Binary complex of the enzyme with its polynucleotide substrate. The distance between the active site of the polymerase domain and the RNase H domain is shown by arrows.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig02
Figure 2.
Spatial constraints for drug design. (A) Simplified scheme of the catalytic reaction of phosphoryl transfer. The hydroxyl at the 3’ end of the primer attacks the α-phosphate of the incoming nucleotide. Two metal ions (designated A and B) stabilize the positioning of the triphosphate group, in coordination with the aspartic acids (bottom) and two positively charged residues (top). (B) Targeted sites for modifications on nucleosides.
10.1128/9781555815493/f0054-01_thmb.gif
10.1128/9781555815493/f0054-01.gif
Figure 2.
Spatial constraints for drug design. (A) Simplified scheme of the catalytic reaction of phosphoryl transfer. The hydroxyl at the 3’ end of the primer attacks the α-phosphate of the incoming nucleotide. Two metal ions (designated A and B) stabilize the positioning of the triphosphate group, in coordination with the aspartic acids (bottom) and two positively charged residues (top). (B) Targeted sites for modifications on nucleosides.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig03
Figure 3.
Chemical structures of currently approved NRTIs.
10.1128/9781555815493/f0055-01_thmb.gif
10.1128/9781555815493/f0055-01.gif
Figure 3.
Chemical structures of currently approved NRTIs.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig04
Figure 4.
Route of metabolic activation of NRTIs by kinases. Examples of activation of AZT and tenofovir show the number of steps required to generate the corresponding active nucleotides prior to chain termination.
10.1128/9781555815493/f0056-01_thmb.gif
10.1128/9781555815493/f0056-01.gif
Figure 4.
Route of metabolic activation of NRTIs by kinases. Examples of activation of AZT and tenofovir show the number of steps required to generate the corresponding active nucleotides prior to chain termination.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig05
Figure 5.
NRTI resistance (adapted from reference
42a
).
10.1128/9781555815493/f0058-01_thmb.gif
10.1128/9781555815493/f0058-01.gif
Figure 5.
NRTI resistance (adapted from reference 42a ).
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig06
Figure 6.
Reaction scheme for NRTI incorporation and drug resistance. After formation of the nucleoprotein complex (E*DNAn), chain termination by NRTIs at position DNAn+1 requires an initial binding step [measured by Kd
(NRTI)], followed by a catalytic step (kpol
) with PPi as a side product (
43
). Mutations such as M184V (Kd
effect) or K65R (kpol
effect) confer resistance of HIV-1 RT by discriminating against NRTIs. On the other hand, TAMs increase the pyrophosphorolytic properties of HIV-1 RT, mainly observed on the incorporation of AZT-MP.
10.1128/9781555815493/f0059-01_thmb.gif
10.1128/9781555815493/f0059-01.gif
Figure 6.
Reaction scheme for NRTI incorporation and drug resistance. After formation of the nucleoprotein complex (E*DNAn), chain termination by NRTIs at position DNAn+1 requires an initial binding step [measured by Kd (NRTI)], followed by a catalytic step (kpol ) with PPi as a side product ( 43 ). Mutations such as M184V (Kd effect) or K65R (kpol effect) confer resistance of HIV-1 RT by discriminating against NRTIs. On the other hand, TAMs increase the pyrophosphorolytic properties of HIV-1 RT, mainly observed on the incorporation of AZT-MP.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig07
Figure 7.
Scheme of enzyme positioning on its nucleic acid substrate. The nucleotide binding site is occupied by the end of the primer directly after phosphoryl transfer. RT translocates by one base at a time to free the N site prior to each catalytic step.
10.1128/9781555815493/f0061-01_thmb.gif
10.1128/9781555815493/f0061-01.gif
Figure 7.
Scheme of enzyme positioning on its nucleic acid substrate. The nucleotide binding site is occupied by the end of the primer directly after phosphoryl transfer. RT translocates by one base at a time to free the N site prior to each catalytic step.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig08
Figure 8.
Role of the RNase H domain in AZT resistance. Mutations identified in the connection and RNase H domains have been shown to decrease the RNAse H activity. By slowing down the rate of template switching, these mutations increase the residence time of RT, which allows excision of the chain terminator.
10.1128/9781555815493/f0062-01_thmb.gif
10.1128/9781555815493/f0062-01.gif
Figure 8.
Role of the RNase H domain in AZT resistance. Mutations identified in the connection and RNase H domains have been shown to decrease the RNAse H activity. By slowing down the rate of template switching, these mutations increase the residence time of RT, which allows excision of the chain terminator.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
/content/10.1128/9781555815493.ch04.ch04fig09
Figure 9.
Names and chemical structures of NNRTIs in development.
10.1128/9781555815493/f0065-01_thmb.gif
10.1128/9781555815493/f0065-01.gif
Figure 9.
Names and chemical structures of NNRTIs in development.
Citation:
Deval J, Götte M.
2009.
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase,
p 51-70.
In
LaFemina, Ph. D. R (ed),
Antiviral Research.
ASM Press, Washington, DC.
doi: 10.1128/9781555815493.ch4
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