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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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Structure of HIV-1 IN. (A) IN domains,where the catalytic triadis shown in pink. (B–D) Structures of single IN domains: (B)NTD (PDB code 1wje); (C) CCD (PDB code 1bis); (D) CTD (PDB code 1ihv). (E–F) IN two-domain structures:(E) NTD + CCD (PDB code 1k6y); (F) CTD + CCD (PDB code 1ex4). Each structure consists of two IN monomers,shown in yellow and blue. The zinc ions in the NTD are shown in green,and the catalytic triad (D64, D116, and E152) in the CCD is shownin pink.
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fig1: Structure of HIV-1 IN. (A) IN domains,where the catalytic triadis shown in pink. (B–D) Structures of single IN domains: (B)NTD (PDB code 1wje); (C) CCD (PDB code 1bis); (D) CTD (PDB code 1ihv). (E–F) IN two-domain structures:(E) NTD + CCD (PDB code 1k6y); (F) CTD + CCD (PDB code 1ex4). Each structure consists of two IN monomers,shown in yellow and blue. The zinc ions in the NTD are shown in green,and the catalytic triad (D64, D116, and E152) in the CCD is shownin pink.

Mentions: IN is a 32 kDa protein comprising threestructural domains: anN-terminal domain (NTD) (residues 1–50) that contains a zinc-bindingHHCC motif,29 a catalytic core domain (CCD)(residues 51–212) that contains the enzymatic active site andthe catalytic triad (D64, D116, and E152),30 and a C-terminal nonspecific DNA-binding domain (CTD) (residues213–288) (Figure 1).31 The structures of the three individual IN domains havebeen determined,29,31,32 in addition to the structures of the CCD when bound to the NTD33 and CTD.34 All ofthese structures show that IN exists as a dimer or in higher oligomericstates. The interactions between IN subunits are highly dynamic, aproperty that is essential for the biological function of IN.35 The dimerization interface is composed of fourα-helices (α1, residues 95–109; α3, residues123–133; α5, residues 171–187; and α6, residues188–208) and one β-strand (β3, residues 248–252)from each monomer of the CCD. The dimer is stabilized through additionalinteractions between the monomers in the NTD (residues 29–35).34,36 In the CCD, the helix-to-helix contacts between α1 and α5′and between α1′ and α5 contribute to dimer stabilizationby strong hydrophobic and electrostatic interactions.30 Several models of DNA complexed with full-length IN havebeen proposed,37 but the structure of thiscomplex has not yet been solved.


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

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

Structure of HIV-1 IN. (A) IN domains,where the catalytic triadis shown in pink. (B–D) Structures of single IN domains: (B)NTD (PDB code 1wje); (C) CCD (PDB code 1bis); (D) CTD (PDB code 1ihv). (E–F) IN two-domain structures:(E) NTD + CCD (PDB code 1k6y); (F) CTD + CCD (PDB code 1ex4). Each structure consists of two IN monomers,shown in yellow and blue. The zinc ions in the NTD are shown in green,and the catalytic triad (D64, D116, and E152) in the CCD is shownin pink.
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Related In: Results  -  Collection

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

fig1: Structure of HIV-1 IN. (A) IN domains,where the catalytic triadis shown in pink. (B–D) Structures of single IN domains: (B)NTD (PDB code 1wje); (C) CCD (PDB code 1bis); (D) CTD (PDB code 1ihv). (E–F) IN two-domain structures:(E) NTD + CCD (PDB code 1k6y); (F) CTD + CCD (PDB code 1ex4). Each structure consists of two IN monomers,shown in yellow and blue. The zinc ions in the NTD are shown in green,and the catalytic triad (D64, D116, and E152) in the CCD is shownin pink.
Mentions: IN is a 32 kDa protein comprising threestructural domains: anN-terminal domain (NTD) (residues 1–50) that contains a zinc-bindingHHCC motif,29 a catalytic core domain (CCD)(residues 51–212) that contains the enzymatic active site andthe catalytic triad (D64, D116, and E152),30 and a C-terminal nonspecific DNA-binding domain (CTD) (residues213–288) (Figure 1).31 The structures of the three individual IN domains havebeen determined,29,31,32 in addition to the structures of the CCD when bound to the NTD33 and CTD.34 All ofthese structures show that IN exists as a dimer or in higher oligomericstates. The interactions between IN subunits are highly dynamic, aproperty that is essential for the biological function of IN.35 The dimerization interface is composed of fourα-helices (α1, residues 95–109; α3, residues123–133; α5, residues 171–187; and α6, residues188–208) and one β-strand (β3, residues 248–252)from each monomer of the CCD. The dimer is stabilized through additionalinteractions between the monomers in the NTD (residues 29–35).34,36 In the CCD, the helix-to-helix contacts between α1 and α5′and between α1′ and α5 contribute to dimer stabilizationby strong hydrophobic and electrostatic interactions.30 Several models of DNA complexed with full-length IN havebeen proposed,37 but the structure of thiscomplex has not yet been solved.

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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