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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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Designof early RAL-like inhibitors: from HCV polymerase to HIVIN inhibitors.
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fig5: Designof early RAL-like inhibitors: from HCV polymerase to HIVIN inhibitors.

Mentions: DKA bioisosterswere also proven to bind divalent cations,76 and several studies have been performed to betterdefine the mechanism of action of DKA bioisosters, which includedthe study that reported 4 and 5. This studydemonstrated that the IN–vDNA complex was “trapped”by these ST inhibitors via a transient intermediate within the PIC.81 The most important class of DKA bioisoster hasbeen designed and reported by a Merck team in IRBM in Rome. IRBM hadbeen studying the inhibitors of HCV polymerase and described compoundswith a dihydroxypyrimidinecarboxylic moiety that were also potentINSTIs (Figure 5).82


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

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

Designof early RAL-like inhibitors: from HCV polymerase to HIVIN inhibitors.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Designof early RAL-like inhibitors: from HCV polymerase to HIVIN inhibitors.
Mentions: DKA bioisosterswere also proven to bind divalent cations,76 and several studies have been performed to betterdefine the mechanism of action of DKA bioisosters, which includedthe study that reported 4 and 5. This studydemonstrated that the IN–vDNA complex was “trapped”by these ST inhibitors via a transient intermediate within the PIC.81 The most important class of DKA bioisoster hasbeen designed and reported by a Merck team in IRBM in Rome. IRBM hadbeen studying the inhibitors of HCV polymerase and described compoundswith a dihydroxypyrimidinecarboxylic moiety that were also potentINSTIs (Figure 5).82

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