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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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Outline of the in vivo integration process.
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fig3: Outline of the in vivo integration process.

Mentions: For HlV-l IN, severalexperiments have established that the integrationprocess consists of two catalytic steps: the first step is 3′-P,a hydrolysis step, followed by strand transfer (ST), a transesterificationstep (Figure 3),44,45 in which twohighly cooperative divalent cations catalyze these two reactions centeredon a phosphodiester bond. A long debate regarding the nature and thenumber of divalent cations that are involved as cofactors has persisted.It is not clear whether both metals are present within CCD or if thesecond metal is brought by the incoming vDNA, even though the twometal ions cooperate in the catalysis of IN. However, the IN catalyticDDE triad coordinates metal ions such as Mn2+ or Mg2+, with the latter assumed to be the physiologically relevantspecies.46


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

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

Outline of the in vivo integration process.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Outline of the in vivo integration process.
Mentions: For HlV-l IN, severalexperiments have established that the integrationprocess consists of two catalytic steps: the first step is 3′-P,a hydrolysis step, followed by strand transfer (ST), a transesterificationstep (Figure 3),44,45 in which twohighly cooperative divalent cations catalyze these two reactions centeredon a phosphodiester bond. A long debate regarding the nature and thenumber of divalent cations that are involved as cofactors has persisted.It is not clear whether both metals are present within CCD or if thesecond metal is brought by the incoming vDNA, even though the twometal ions cooperate in the catalysis of IN. However, the IN catalyticDDE triad coordinates metal ions such as Mn2+ or Mg2+, with the latter assumed to be the physiologically relevantspecies.46

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