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Inhibiting the HIV integration process: past, present, and the future.

Di Santo R - J. Med. Chem. (2013)

Bottom Line: The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported.The role played by the resistance is elucidated, as well as the possibility of bypassing this problem.New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur, Fondazione Cenci Bolognetti, "Sapienza" Università di Roma , P.le Aldo Moro 5, I-00185 Rome, Italy.

ABSTRACT
HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

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(A) LEDGF/p75 domains:N-terminal PWWP motif and the charged regions(CR1–3) critical for chromatin recognition and the centralDNA binding domain (blue) and the C-terminal IBD (magenta) essentialfor binding to IN and cellular proteins. (B) Cocrystallized structureof LEDGF/p75–IBD (magenta) and the CCD dimer of integrase (greenand blue). The catalytic triad is represented in orange (PDB code 2B4J). (C) Cartoon focusedon CCD–IBD binding (PDB code 2B4J). IN CCDs are shown in green and blue,whereas the LEDGF/p75 IBD is in magenta. Residues of IN (dark green)and IBD (magenta) critical for the interaction are highlighted.
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fig7: (A) LEDGF/p75 domains:N-terminal PWWP motif and the charged regions(CR1–3) critical for chromatin recognition and the centralDNA binding domain (blue) and the C-terminal IBD (magenta) essentialfor binding to IN and cellular proteins. (B) Cocrystallized structureof LEDGF/p75–IBD (magenta) and the CCD dimer of integrase (greenand blue). The catalytic triad is represented in orange (PDB code 2B4J). (C) Cartoon focusedon CCD–IBD binding (PDB code 2B4J). IN CCDs are shown in green and blue,whereas the LEDGF/p75 IBD is in magenta. Residues of IN (dark green)and IBD (magenta) critical for the interaction are highlighted.

Mentions: LEDGF is a transcriptionalregulatory protein that is stronglyassociated with chromatin throughout the cell cycle. It is expressedas two spliced variants: the LEDGF/p52 and LEDGF/p75 proteins.146 LEDGF comprises several functional domainsimplicated in the integration process. The N-terminus contains thePWWP (proline–tryptophan–tryptophan–proline)domain, three charged domains, the nuclear localization signal (NLS),and dual copies of the AT-hook DNA-binding motif.147 The C-terminus is different for the splicing variants:LEDGF/p75 shows a more extended domain that includes the integrase-bindingdomain (IBD), which was crucial for specific interaction with HIV-1IN (Figure 7A).147 This protein was identified as an interaction partner of HIV-1 INin human cells148 and has been shown tostimulate the in vitro integration activity of IN (Figure 6).149


Inhibiting the HIV integration process: past, present, and the future.

Di Santo R - J. Med. Chem. (2013)

(A) LEDGF/p75 domains:N-terminal PWWP motif and the charged regions(CR1–3) critical for chromatin recognition and the centralDNA binding domain (blue) and the C-terminal IBD (magenta) essentialfor binding to IN and cellular proteins. (B) Cocrystallized structureof LEDGF/p75–IBD (magenta) and the CCD dimer of integrase (greenand blue). The catalytic triad is represented in orange (PDB code 2B4J). (C) Cartoon focusedon CCD–IBD binding (PDB code 2B4J). IN CCDs are shown in green and blue,whereas the LEDGF/p75 IBD is in magenta. Residues of IN (dark green)and IBD (magenta) critical for the interaction are highlighted.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926363&req=5

fig7: (A) LEDGF/p75 domains:N-terminal PWWP motif and the charged regions(CR1–3) critical for chromatin recognition and the centralDNA binding domain (blue) and the C-terminal IBD (magenta) essentialfor binding to IN and cellular proteins. (B) Cocrystallized structureof LEDGF/p75–IBD (magenta) and the CCD dimer of integrase (greenand blue). The catalytic triad is represented in orange (PDB code 2B4J). (C) Cartoon focusedon CCD–IBD binding (PDB code 2B4J). IN CCDs are shown in green and blue,whereas the LEDGF/p75 IBD is in magenta. Residues of IN (dark green)and IBD (magenta) critical for the interaction are highlighted.
Mentions: LEDGF is a transcriptionalregulatory protein that is stronglyassociated with chromatin throughout the cell cycle. It is expressedas two spliced variants: the LEDGF/p52 and LEDGF/p75 proteins.146 LEDGF comprises several functional domainsimplicated in the integration process. The N-terminus contains thePWWP (proline–tryptophan–tryptophan–proline)domain, three charged domains, the nuclear localization signal (NLS),and dual copies of the AT-hook DNA-binding motif.147 The C-terminus is different for the splicing variants:LEDGF/p75 shows a more extended domain that includes the integrase-bindingdomain (IBD), which was crucial for specific interaction with HIV-1IN (Figure 7A).147 This protein was identified as an interaction partner of HIV-1 INin human cells148 and has been shown tostimulate the in vitro integration activity of IN (Figure 6).149

Bottom Line: The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported.The role played by the resistance is elucidated, as well as the possibility of bypassing this problem.New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur, Fondazione Cenci Bolognetti, "Sapienza" Università di Roma , P.le Aldo Moro 5, I-00185 Rome, Italy.

ABSTRACT
HIV integrase (IN) catalyzes the insertion into the genome of the infected human cell of viral DNA produced by the retrotranscription process. The discovery of raltegravir validated the existence of the IN, which is a new target in the field of anti-HIV drug research. The mechanism of catalysis of IN is depicted, and the characteristics of the inhibitors of the catalytic site of this viral enzyme are reported. The role played by the resistance is elucidated, as well as the possibility of bypassing this problem. New approaches to block the integration process are depicted as future perspectives, such as development of allosteric IN inhibitors, dual inhibitors targeting both IN and other enzymes, inhibitors of enzymes that activate IN, activators of IN activity, as well as a gene therapy approach.

Show MeSH