Mechanisms and inhibition of HIV integration

Marchand, Christophe; Johnson, Allison A.; Семенова, Е. А.; Pommier, ﻿Yves

doi:10.1016/j.ddmec.2006.05.004

Cited by 27 publications

(20 citation statements)

References 51 publications

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“…The present review describes recent advances in the search for HIV-1 IN inhibitors with a focus on the mechanism of inhibition by diketo acids and small molecules, natural products, peptides, antibody and oligonucleotide inhibitors published in the last two years. It is an update of our prior landmark reviews 5, 6 and complements other recent reviews 7–22.…”

Section: Introductionmentioning

confidence: 87%

HIV-1 IN Inhibitors: 2010 Update and Perspectives

Marchand¹,

Maddali²,

Métifiot³

et al. 2009

CTMC

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Integrase (IN) is the newest validated target against AIDS and retroviral infections. The remarkable activity of raltegravir (Isentress ® ) led to its rapid approval by the FDA in 2007 as the first IN inhibitor. Several other IN strand transfer inhibitors (STIs) are in development with the primary goal to overcome resistance due to the rapid occurrence of IN mutations in raltegravirtreated patients. Thus, many scientists and drug companies are actively pursuing clinically useful IN inhibitors. The objective of this review is to provide an update on the IN inhibitors reported in the last two years, including second generation strand transfer inhibitors (STI), recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors. Additionally, the targeting of IN cofactors such as LEDGF and Vpr will be discussed as novel strategies for the treatment of AIDS.

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Section: Introductionmentioning

confidence: 87%

HIV-1 IN Inhibitors: 2010 Update and Perspectives

Marchand¹,

Maddali²,

Métifiot³

et al. 2009

CTMC

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“…This releases a terminal 5Ј-GT dinucleotide from the end of each viral long terminal repeat (LTR) in a reaction called 3Ј-processing (3Ј-P). Subsequently, the viral and host DNAs are joined by insertion of both nucleophilic viral cDNA 3Ј-hydroxyl ends into a host chromosome (termed strand transfer, ST) (Lewinski and Bushman, 2005;Pommier et al, 2005;Van Maele and Debyser, 2005;Marchand et al, 2006). Despite many attempts, no crystal structure of integrase bound to its DNA substrates has been resolved.…”

mentioning

confidence: 99%

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Johnson¹,

Marchand²,

Patil³

et al. 2006

Mol Pharmacol

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HIV-1 integrase binds site-specifically to the ends of the viral cDNA. We used two HIV-1 integrase-DNA cross-linking assays to probe the binding sites of integrase inhibitors from different chemical families and with different strand transfer selectivities. The disulfide assay probes cross-linking between the integrase residue 148 and the 5Ј-terminal cytosine of the viral cDNA, and the Schiff base assay probes cross-linking between an integrase lysine residue and an abasic site placed at selected positions in the viral cDNA. Cross-linking interference by eight integrase inhibitors shows that the most potent cross-linking inhibitors are 3Ј-processing inhibitors, indicating that crosslinking assays probe the donor viral cDNA (donor binding site). In contrast, strand transfer-selective inhibitors provide weak cross-linking interference, consistent with their binding to a specific acceptor (cellular DNA) site. Docking and crystal structure studies illustrate specific integrase-inhibitor contacts that prevent cross-linking formation. Four inhibitors that prevented Schiff base cross-linking to the conserved 3Ј-terminal adenine position were examined for inhibition at various positions within the terminal 21 bases of the viral cDNA. Two of them selectively inhibited upper strand cross-linking, whereas the other two had a more global effect on integrase-DNA binding. These findings have implications for elucidating inhibitor binding sites and mechanisms of action. The cross-linking assays also provide clues to the molecular interactions between integrase and the viral cDNA.

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“…Nevertheless, Zn 2+ was found to promote multimerization indicating that the NTD as well is important for protein-protein interactions [163,318]. Experimental data point towards a tetramer as the minimal active form of IN [185]. Cross-linked tetramers could catalyze full-site integration in vitro while dimers could integrate just one viral LTR end to the target DNA [93].…”

Section: Structure and Function Of Hiv Integrasementioning

confidence: 90%

HIV-1 Integrase: From Biology to Chemotherapeutics

Zeinalipour-Loizidou

Nicolaou²,

Nicolaides³

et al. 2007

CHR

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AIDS has claimed the lives of 25 million people worldwide, an additional 40 million people are HIV-infected and new cases are being diagnosed every year. Despite the fact that HAART has moved AIDS from the category of terminal diseases to that of treatable chronic illnesses, its long-term therapeutic success may be compromised by the development of resistance to the currently used drugs. Despite the availability of RT, PR and fusion inhibitors, the development of further drugs such as inhibitors that target the third enzyme IN is essential for the clinical management of HIV-infected patients. The absence of cellular homolgues to IN and the unique nature of the reactions catalyzed by IN, make it an ideal target for drug design. Considerable progress towards designing HIV-1 IN inhibitors has been made over the last years and several lead compounds have been identified, synthesized and clinically studied. This review focuses on the existing knowledge of the biology of HIV-1 IN with emphasis on the mechanism of integration, structure and function and the technologies for measuring IN activity. This is followed by the current trends on designing HIV-1 IN inhibitors with the aid of molecular informatics and a review on the main classes of HIV-1 IN inhibitors reported this far with special emphasis on the clinical candidates.

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Mechanisms and inhibition of HIV integration

Cited by 27 publications

References 51 publications

HIV-1 IN Inhibitors: 2010 Update and Perspectives

HIV-1 IN Inhibitors: 2010 Update and Perspectives

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

HIV-1 Integrase: From Biology to Chemotherapeutics

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