Targeting the Viral Nucleocapsid Protein in Anti-HIV-1 Therapy

Mély, Yves; Rocquigny, Hugues de; Shvadchak, Volodymyr V.; Avilov, Sergiy V.; Dong, Chunhui; Dietrich, Ursula; Darlix, Jean‐Luc

doi:10.2174/138955708783331603

Cited by 74 publications

(26 citation statements)

References 79 publications

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“…Such an intracellular DNA synthesis during virus assembly producing HIV-1 DNA-containing particles could be the source of HIV-1 re-emergence when antiviral therapy is halted. Our findings may complement ongoing efforts to block HIV replication with anti-NC drugs (1,63,64) and may also identify new strategies for the design of antiviral therapies.…”

Section: Discussionmentioning

confidence: 65%

The conserved N-terminal basic residues and zinc-finger motifs of HIV-1 nucleocapsid restrict the viral cDNA synthesis during virus formation and maturation

Didierlaurent

Houzet

Morichaud

et al. 2008

Nucleic Acids Research

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Reverse transcription of the genomic RNA by reverse transcriptase occurs soon after HIV-1 infection of target cells. The viral nucleocapsid (NC) protein chaperones this process via its nucleic acid annealing activities and its interactions with the reverse transcriptase enzyme. To function, NC needs its two conserved zinc fingers and flanking basic residues. We recently reported a new role for NC, whereby it negatively controls reverse transcription in the course of virus formation. Indeed, deleting its zinc fingers causes reverse transcription activation in virus producer cells. To investigate this new NC function, we used viruses with subtle mutations in the conserved zinc fingers and its flanking domains. We monitored by quantitative PCR the HIV-1 DNA content in producer cells and in produced virions. Results showed that the two intact zinc-finger structures are required for the temporal control of reverse transcription by NC throughout the virus replication cycle. The N-terminal basic residues also contributed to this new role of NC, while Pro-31 residue between the zinc fingers and Lys-59 in the C-terminal region did not. These findings further highlight the importance of NC as a major target for anti-HIV-1 drugs.

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Section: Discussionmentioning

confidence: 65%

The conserved N-terminal basic residues and zinc-finger motifs of HIV-1 nucleocapsid restrict the viral cDNA synthesis during virus formation and maturation

Didierlaurent

Houzet

Morichaud

et al. 2008

Nucleic Acids Research

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“…Various categories of compounds in this class were reported during the 1990s, including 3-nitrosobenzamide (NOBA) (Rice et al, 1993), 2,2’-dithiobisbenzamide (DIBA) (Rice et al, 1995), cyclic 2,2’- dithiobisbenzamide (Witvrouw et al, 1997), 1,2-dithiane-4,5-diol-1,1-dioxide (Rice et al, 1997a), azadicarbonamide (ADA) (Rice et al, 1997b) and pyridinioalkanoyl 2-mercaptobenzamide thioesters (PATE) (Turpin et al, 1999). The structure and activity of these zinc ejectors has been reviewed by Rocquigny et al (de Rocquigny et al, 2008). Some of these molecules, such as DIBA-1, dithiane and ADA, were selective to HIV NC, with limited interaction with endogenous cellular zinc fingers (Huang et al, 1998).…”

Section: Zinc Finger Bindersmentioning

confidence: 99%

“…However, the compounds did not compete with the pre-bound DNA on NC. The two hydroxyl substitutions on the xanthenyl ring, which are thought to interact with the backbone atoms of Lys33, Gly35 and Gly40, were found to be critical for binding to NC and for providing protection against HIV infection (de Rocquigny et al, 2008). …”

Section: Zinc Finger Bindersmentioning

confidence: 99%

Advances in targeting nucleocapsid–nucleic acid interactions in HIV-1 therapy

Garg

Torbett

2014

Virus Research

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The continuing challenge of HIV-1 treatment resistance in patients creates a need for the development of new antiretroviral inhibitors. The HIV nucleocapsid (NC) protein is a potential therapeutic target. NC is necessary for viral RNA packaging and in the early stages of viral infection. The high level of NC amino acid conservation among all HIV-1 clades suggests a low tolerance for mutations. Thus, NC mutations that could arise during inhibitor treatment to provide resistance may render the virus less fit. Disruption of NC function provides a unique opportunity to strongly dampen replication at multiple points during the viral life cycle with a single inhibitor. Although NC exhibits desirable features for a potential antiviral target, the structural flexibility, size, and the presence of two zinc fingers makes small molecule targeting of NC a challenging task. In this review, we discuss the recent advances in strategies to develop inhibitors of NC function and present a perspective on potential novel approaches that may help to overcome some of the current challenges in the field.

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“…It is not surprising therefore that NC has been the target of attempts to develop antiretroviral drugs. Molecules that inhibit zinc incorporation in the NC zinc fingers will not be discussed here but have been previously reviewed [140–141]. NC has in general proven to be a very difficult drug target to date.…”

Section: Inhibitors Targeting Gag Assembly Processes and Maturationmentioning

confidence: 99%

HIV-1 Gag as an Antiviral Target: Development of Assembly and Maturation Inhibitors

Spearman¹

2015

CTMC

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HIV-1 Gag is the master orchestrator of particle assembly. The central role of Gag at multiple stages of the HIV lifecycle has led to efforts to develop drugs that directly target Gag and prevent the formation and release of infectious particles. Until recently, however, only the catalytic site protease inhibitors have been available to inhibit late stages of HIV replication. This review summarizes the current state of development of antivirals that target Gag or disrupt late events in the retrovirus lifecycle such as maturation of the viral capsid. Maturation inhibitors represent an exciting new series of antiviral compounds, including those that specifically target CA-SP1 cleavage and the allosteric integrase inhibitors that inhibit maturation by a completely different mechanism. Numerous small molecules and peptides targeting CA have been studied in attempts to disrupt steps in assembly. Efforts to target CA have recently gained have considerable momentum from the development of small molecules that bind CA and alter capsid stability at the post-entry stage of the lifecycle. Efforts to develop antivirals that inhibit incorporation of genomic RNA or to inhibit late budding events remain in preliminary stages of development. Overall, the development of novel antivirals targeting Gag and the late stages in HIV replication appears much closer to success than ever, with the new maturation inhibitors leading the way.

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Targeting the Viral Nucleocapsid Protein in Anti-HIV-1 Therapy

Cited by 74 publications

References 79 publications

The conserved N-terminal basic residues and zinc-finger motifs of HIV-1 nucleocapsid restrict the viral cDNA synthesis during virus formation and maturation

The conserved N-terminal basic residues and zinc-finger motifs of HIV-1 nucleocapsid restrict the viral cDNA synthesis during virus formation and maturation

Advances in targeting nucleocapsid–nucleic acid interactions in HIV-1 therapy

HIV-1 Gag as an Antiviral Target: Development of Assembly and Maturation Inhibitors

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