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

Related in: MedlinePlus

Architecture of the PFVintasome. (A) Views along (left) and perpendicular(right) to the crystallographic 2-fold axis. The subunits of the INtetramer, which are in blue and green, are engaged with viral DNA.The external IN chains are in yellow. The DNA strands are orange andmagenta, and the last one is the most reactive. D128, D185, E221,or the catalytic triad is in red. Gray spheres are Zn atoms. (B) Focuson IN chains with domains and linkers indicated.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Architecture of the PFVintasome. (A) Views along (left) and perpendicular(right) to the crystallographic 2-fold axis. The subunits of the INtetramer, which are in blue and green, are engaged with viral DNA.The external IN chains are in yellow. The DNA strands are orange andmagenta, and the last one is the most reactive. D128, D185, E221,or the catalytic triad is in red. Gray spheres are Zn atoms. (B) Focuson IN chains with domains and linkers indicated.

Mentions: Recently, the crystal structureof the DNA-bound full-length prototypefoamy virus (PFV) was determined.38 Thisstructure was used to establish the model for full-length HIV-1 INwhen bound to DNA.39 In this model, a tetramerof IN is attached to a pair of vDNA molecules. The CCD retains theknown dimeric interface,30,40 but only two of thefour active sites in the tetramer, one from each CCD dimer, associatewith the vDNA. Both the NTD and the CTD contribute to the stabilizationof the tetramer (Figure 2).


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

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

Architecture of the PFVintasome. (A) Views along (left) and perpendicular(right) to the crystallographic 2-fold axis. The subunits of the INtetramer, which are in blue and green, are engaged with viral DNA.The external IN chains are in yellow. The DNA strands are orange andmagenta, and the last one is the most reactive. D128, D185, E221,or the catalytic triad is in red. Gray spheres are Zn atoms. (B) Focuson IN chains with domains and linkers indicated.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Architecture of the PFVintasome. (A) Views along (left) and perpendicular(right) to the crystallographic 2-fold axis. The subunits of the INtetramer, which are in blue and green, are engaged with viral DNA.The external IN chains are in yellow. The DNA strands are orange andmagenta, and the last one is the most reactive. D128, D185, E221,or the catalytic triad is in red. Gray spheres are Zn atoms. (B) Focuson IN chains with domains and linkers indicated.
Mentions: Recently, the crystal structureof the DNA-bound full-length prototypefoamy virus (PFV) was determined.38 Thisstructure was used to establish the model for full-length HIV-1 INwhen bound to DNA.39 In this model, a tetramerof IN is attached to a pair of vDNA molecules. The CCD retains theknown dimeric interface,30,40 but only two of thefour active sites in the tetramer, one from each CCD dimer, associatewith the vDNA. Both the NTD and the CTD contribute to the stabilizationof the tetramer (Figure 2).

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
Related in: MedlinePlus