Limits...
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.

Show MeSH
Regulation of HIV-1 integrationby the acetylation and deacetylationof IN.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3926363&req=5

fig9: Regulation of HIV-1 integrationby the acetylation and deacetylationof IN.

Mentions: Althoughthe association between PTMs and the retroviral integrationprocess has not been fully addressed, it was revealed that HAT p300regulates the viral expression of both DNA viruses and lentiviruses;208 the enzymatic activity of HIV-1 IN is positivelyregulated by both p300 and GCN5 HATs (Figure 9).209 A specific interaction between HATp300 and IN both in vitro and in vivo has been described.209a The authors demonstrated that endogenous p300co-immuno-precipitated with IN when using a codon-optimized flag-taggedIN. HAT p300 was found to acetylate IN at residues K264, K266, andK273 within the IN C-terminus both in vitro and in vivo. The acetylationof IN increased its affinity for DNA and enhanced its ST activitywithout influencing the 3′-P catalytic activity in vitro. HATGCN5 was found to mediate the acetylation of HIV-1 IN at the sameC-terminal lysines as p300, and HIV-1 integration was shown to beimpaired in GCN5 knockdown cells.209b


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

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

Regulation of HIV-1 integrationby the acetylation and deacetylationof IN.
© Copyright Policy
Related In: Results  -  Collection

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

fig9: Regulation of HIV-1 integrationby the acetylation and deacetylationof IN.
Mentions: Althoughthe association between PTMs and the retroviral integrationprocess has not been fully addressed, it was revealed that HAT p300regulates the viral expression of both DNA viruses and lentiviruses;208 the enzymatic activity of HIV-1 IN is positivelyregulated by both p300 and GCN5 HATs (Figure 9).209 A specific interaction between HATp300 and IN both in vitro and in vivo has been described.209a The authors demonstrated that endogenous p300co-immuno-precipitated with IN when using a codon-optimized flag-taggedIN. HAT p300 was found to acetylate IN at residues K264, K266, andK273 within the IN C-terminus both in vitro and in vivo. The acetylationof IN increased its affinity for DNA and enhanced its ST activitywithout influencing the 3′-P catalytic activity in vitro. HATGCN5 was found to mediate the acetylation of HIV-1 IN at the sameC-terminal lysines as p300, and HIV-1 integration was shown to beimpaired in GCN5 knockdown cells.209b

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