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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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Schematic representation of the LEDGF supportof the HIV-1 integrationprocess. On the right, the different mechanisms of inhibition by LEDGINs(up) and INSTIs (down) are described. Inhibitors are represented inred.
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fig8: Schematic representation of the LEDGF supportof the HIV-1 integrationprocess. On the right, the different mechanisms of inhibition by LEDGINs(up) and INSTIs (down) are described. Inhibitors are represented inred.

Mentions: LEDGF is the first cellular proteindemonstrated to be a bona fidecofactor for HIV-1 integration.147 It playsa critical, but not strictly essential, role. A significant reductionof HIV-1 replication in human CD4+ T cells with a knockdownof endogenous LEDGF was demonstrated.150 Additionally, a knockout study performed in mouse embryonic fibroblastscell lines reported a 90% reduction in HIV-1 infectivity upon thedepletion of LEDGF/p75, which was recovered upon the re-expressionof LEDGF.151 The blockage of HIV-1 infectionwas shown to occur specifically at the integration step, and boththe PWWP and IBD domains were proven to be of critical importancefor HIV-1 integration and replication.150,151 On the basisof these findings, LEDGF is proposed to be a molecular adaptor thattethers HIV-1 IN to the target DNA. Because LEDGF is a transcriptionalcoactivator, this tethering activity might be responsible for targetingthe integration site of HIV-1 toward transcriptionally active regions(Figure 8).147


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

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

Schematic representation of the LEDGF supportof the HIV-1 integrationprocess. On the right, the different mechanisms of inhibition by LEDGINs(up) and INSTIs (down) are described. Inhibitors are represented inred.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Schematic representation of the LEDGF supportof the HIV-1 integrationprocess. On the right, the different mechanisms of inhibition by LEDGINs(up) and INSTIs (down) are described. Inhibitors are represented inred.
Mentions: LEDGF is the first cellular proteindemonstrated to be a bona fidecofactor for HIV-1 integration.147 It playsa critical, but not strictly essential, role. A significant reductionof HIV-1 replication in human CD4+ T cells with a knockdownof endogenous LEDGF was demonstrated.150 Additionally, a knockout study performed in mouse embryonic fibroblastscell lines reported a 90% reduction in HIV-1 infectivity upon thedepletion of LEDGF/p75, which was recovered upon the re-expressionof LEDGF.151 The blockage of HIV-1 infectionwas shown to occur specifically at the integration step, and boththe PWWP and IBD domains were proven to be of critical importancefor HIV-1 integration and replication.150,151 On the basisof these findings, LEDGF is proposed to be a molecular adaptor thattethers HIV-1 IN to the target DNA. Because LEDGF is a transcriptionalcoactivator, this tethering activity might be responsible for targetingthe integration site of HIV-1 toward transcriptionally active regions(Figure 8).147

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