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Integrase inhibitors to treat HIV/Aids

Key Points

  • HIV-1 integrase is a rational target for anti-HIV therapy, and the feasibility and efficacy of integrase inhibitors in animal models has been recently demonstrated.

  • Integrase catalyses the insertion of the viral cDNA ends generated by reverse transcription of the viral RNA genome into host chromosomes. The integration reaction consists of two consecutive steps: 3′-processing and strand transfer.

  • Several structures of retroviral integrases have been solved. Integrase is structurally similar to other DNA-processing polynucleotide transferases, including the Tn5 and mu transposases, RuvC recombinase, RnaseH and the RNase component Argonaute. All of these contain a conserved DDE motif required for enzymatic activity. Divalent metals (almost certainly at least one, and probably two, Mg2+ or Mn2+ atoms) coordinate the integrase DDE motif, the viral cDNA and chromosomal DNA for the integration reactions.

  • Integrase can be used for high-throughput screening and a variety of inhibitors from diverse chemical classes have been identified. Criteria required to demonstrate targeting of cellular integrase are reviewed.

  • Diketo acids and diketo-like acids are the most promising integrase inhibitors. They are referred to as strand-transfer inhibitors because they uncouple the two integrase reactions. They can block strand transfer without affecting 3′-processing by chelating divalent cofactors in the integrase active site and by interfering with host (acceptor) DNA binding.

  • Strand-transfer inhibitors probably bind at the interface of the integrase–metal cofactor–viral DNA ternary complex by chelating the divalent metal, and thereby interfering with the binding of the chromosomal target DNA. Strand-transfer inhibitors are candidate interfacial inhibitors, and represent a new mechanism of action in drug discovery.

Abstract

HIV integrase is a rational target for treating HIV infection and preventing AIDS. It took approximately 12 years to develop clinically usable inhibitors of integrase, and Phase I clinical trials of integrase inhibitors have just begun. This review focuses on the molecular basis and rationale for developing integrase inhibitors. The main classes of lead compounds are also described, as well as the concept of interfacial inhibitors of protein–nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors.

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Figure 1: The HIV replication cycle and drug targets.
Figure 2: The two integrase catalytic reactions (3′-processing and strand transfer).
Figure 3: HIV-1 integrase dimer crystal structure.
Figure 4: Chemical structures of antiviral integrase inhibitors.
Figure 5: Chemical structures of antiviral integrase inhibitors.
Figure 6: HIV-1 integrase mutations leading to resistance to DKA and naphthyridine carboxamide (DKA-like) inhibitors cluster at the interface between the integrase and DNA.

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Acknowledgements

Y.P. wishes to thank Kurt W. Kohn for longstanding contribution to our molecular pharmacology studies.

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Correspondence to Yves Pommier.

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Y.P. and C.M. are inventors on a number of pending and granted patents relating to HIV-1 integrase inhibitors.

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DATABASES

Entrez Gene

Argonaute

BAF

HMGA1

HSP60

INI1

LEDGF

Matrix

PML

POL

reverse transcriptase

Vpr

Glossary

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY

(HAART). A therapeutic regime that consists of a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with two nucleoside reverse transcriptase inhibitors.

3′-PROCESSING

Integration requires two consecutive steps that are catalysed by integrase: 3′-processing and strand transfer. 3′-processing corresponds to an endonucleolytic cleavage of the 3′-ends of the viral cDNA. This cleavage is sequence-specific and occurs immediately 3' to a conserved CA dinucleotide motif.

STRAND TRANSFER

The second step of the integration reaction, which corresponds to the ligation of the viral 3′-OH cDNA ends (generated by 3′-processing) to the 5′-DNA phosphate of an acceptor DNA (physiologically a host chromosome).

PRE-INTEGRATION COMPLEX

(PIC). A macromolecular complex formed during and after 3′-processing and carrying the 3′-processed viral cDNA ends with viral and cellular proteins to the nucleus, prior to integration.

DISINTEGRATION

The reverse of the strand transfer reaction catalysed by the integrase catalytic core.

ACCEPTOR DNA

The DNA into which the donor DNA is integrated, which physiologically is host chromosomal DNA. Also termed 'target DNA'.

DDE MOTIF

Catalytic triad consisting of two aspartate (DD) amino-acid residues and one glutamate (E). DDE motifs are conserved among integrase, transposase and phosphoryltransferase enzymes. The HIV-1 integrase DDE motif consists of residue D64, D116 and E152.

CHELATION

Coordination of a metal cofactor. In the case of integrase, strand-transfer inhibitors have been proposed to chelate at least one Mg2+ or Mn2+ atom (and probably two) in the DDE motif. The metal serves normally as a 'coordination bridge' between the integrase DDE motif, the viral donor cDNA and the chromosomal acceptor DNA.

DONOR DNA

The viral cDNA containing 3′-hydroxyl ends that act as nucleophilic donors during the strand-transfer reaction.

INTERFACIAL INHIBITOR

Interfacial inhibitors bind at the interface of two or more macromolecules (protein–protein or protein–nucleic acid). The drug takes advantage of transient structural and energetic conditions created by conformational changes in the macromolecular complex that give rise to 'hot spots' for drug binding.

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Pommier, Y., Johnson, A. & Marchand, C. Integrase inhibitors to treat HIV/Aids. Nat Rev Drug Discov 4, 236–248 (2005). https://doi.org/10.1038/nrd1660

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