Structure–activity relationship of neomycin, paromomycin, and neamine–arginine conjugates, targeting HIV-1 gp120–CXCR4 binding step

Borkow, Gadi; Vijayabaskar, V.; Lara, Humberto H; Kalinkovich, Alexander; Lapidot, Aviva

doi:10.1016/s0166-3542(03)00156-6

Cited by 26 publications

(47 citation statements)

References 39 publications

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“…Interestingly, on one hand, we found that tri-argininegentamicin conjugate (R3G) and NeoR6 interact with CXCR4 [220,225] and with HIV-1 TAR RNA [220,223]. However, on the other hand, we did not find mutations in gp120 or in gp41 in R3G resistant isolates (R3G res ) (Borkow and Lapidot, unpublished data), as we did for NeoR6 res isolates [224,232].…”

Section: Aminoglycoside-arginine Conjugates (Aacs)mentioning

confidence: 55%

“…The AACs, efficiently penetrate cells, including neurons, and accumulate intracellularly [219,220,223,224]. The AACs inhibit HIV-1 infection and proliferation in cultured human lymphocytes, displaying low cytotoxicity [220,223,225,226], inhibit gp120-triggered death in human neuroblastoma cells, and cross the blood brain barrier [227]. AACs antagonize some of the extracellular properties of HIV-1 Tat protein, such as increased viral production, induction of CXCR4 chemokine receptor expression, suppression of CD3-activated proliferation of lymphocytes, and upregulation of CD8 receptor [220], indicating that AACs and Tat bind to similar cellular targets.…”

Section: Aminoglycoside-arginine Conjugates (Aacs)mentioning

confidence: 99%

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Multi-targeting the Entrance Door to Block HIV-1

Borkow¹,

Lapidot

2005

CDTID

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The multistep nature of HIV-1 entry provides multisite targeting at the entrance door of HIV-1 to cells. Blocking HIV-1 entry to its host cells has clear advantages over blocking subsequent stages in the life cycle of the virus. Indeed, potent cooperative and synergistic inhibition of HIV-1 proliferation has been observed in in vitro studies with several entry inhibitor combinations, interacting with different steps of the HIV-1-cell entry cascade. Targeting a compound to several steps of the viral-cell entry and also to subsequent steps in the viral life cycle promises an even more effective therapeutic, by reducing the probability of HIV-1 to develop resistance. Using one drug that can target multiple sites and/or steps in the viral life cycle will have obvious advantages in clinical use. In this article we review the multistep process of HIV-1 cell entry and the current repertoire of inhibitors of this critical stage in the viral life cycle, and introduce an example of multisite HIV-1 targeting of the cell entry and subsequent critical steps in the viral life cycle.

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Section: Aminoglycoside-arginine Conjugates (Aacs)mentioning

confidence: 55%

Section: Aminoglycoside-arginine Conjugates (Aacs)mentioning

confidence: 99%

Multi-targeting the Entrance Door to Block HIV-1

Borkow¹,

Lapidot

2005

CDTID

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“…Multi-arginine-aminoglycoside (AAC) conjugates similarly inhibit HIV-1 replication, presumably via interference with gp120-CXCR4 interaction in addition to their ability to antagonize Tat activity [13]. These compounds effectively competed with 12G5 (a monoclonal anti-CXCR4 antibody), SDF-1α and soluble gp120 in their ability to bind to CXCR4.…”

Section: Gp120-cxcr4 Interaction As An Entry Targetmentioning

confidence: 99%

“…The most potent AAC is the hexa-arginine-neomycin (NeoR6), while other multiarginine-aminoglycoside conjugates proved to be less active with the mono-arginine conjugates displaying the lowest potency. Using continuous HIV-1 passage in the presence of increasing concentrations of NeoR6, investigators were able to select drug-resistant strains of HIV-1 displaying three mutations in gp120, including T746C, C848T and C916A, which conferred resistance [13].…”

Section: Gp120-cxcr4 Interaction As An Entry Targetmentioning

confidence: 99%

“…They can act against both free virus and infected cells and, thus, provide protection by a number of different mechanisms (reviewed in [13,15,132,133]). Neutralizing antibodies generally inhibit entry by preventing virus attachment to the cell or by binding to entry intermediates (reviewed in [16,31,40]).…”

Section: Use Of Monoclonal Antibodies To Inhibit Hiv-1 Entrymentioning

confidence: 99%

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Recent Advances in Understanding the Molecular Mechanisms of HIV-1 Entry and Fusion: Revisiting Current Targets and Considering New Options for Therapeutic Intervention

Markovic¹,

Clouse²

2004

CHR

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Recent advances in our understanding of the cellular and molecular mechanisms of HIV-1 entry provide the basis for novel therapeutic strategies that prevent viral penetration of the target cell-membrane, while reducing detrimental virus and treatment effects on cells and prolonging virion exposure to immune defenses. A number of potential sites for therapeutic intervention become accessible during the narrow window between virus attachment and the subsequent fusion of viral envelope with the cell membrane. Initial approaches considered for prevention of HIV-1 entry included the use of natural ligands, small-molecule inhibitors and/or monoclonal antibodies, which could interfere with gp120-CD4 and/or gp120-CXCR4/CCR5 interaction. Others avenues pursued were the use of agents that interfere with the conformational changes of gp120 or gp41 leading to subsequent fusion of viral and cellular membranes. More recently, strategies have emerged that involve inhibition of thiol/disulfide oxidoreductases (factors which facilitate Env transition from an inactive to a fusion-competent conformation) to block redox exchange, thereby impeding the entry process. This review provides a summary of the cellular and viral factors mediating the HIV-1 entry process, with an emphasis on novel therapeutics targeting Env-receptor/coreceptor interaction, Env conformational change and the membrane fusion process.

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The Future of Aminoglycosides: The End or Renaissance?

et al. 2010

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Although aminoglycosides have been used as antibacterials for decades, their use has been hindered by their inherent toxicity and the resistance that has emerged to these compounds. It seems that such issues have relegated a formerly front-line class of antimicrobials to the proverbial back shelf. However, recent advances have demonstrated that novel aminoglycosides have a potential to overcome resistance as well as to be used to treat HIV-1 and even human genetic disorders, with abrogated toxicity. It is not the end for aminoglycosides, but rather, the challenges faced by researchers have led to ingenuity and a change in how we view this class of compounds, a renaissance.

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Structure–activity relationship of neomycin, paromomycin, and neamine–arginine conjugates, targeting HIV-1 gp120–CXCR4 binding step

Cited by 26 publications

References 39 publications

Multi-targeting the Entrance Door to Block HIV-1

Multi-targeting the Entrance Door to Block HIV-1

Recent Advances in Understanding the Molecular Mechanisms of HIV-1 Entry and Fusion: Revisiting Current Targets and Considering New Options for Therapeutic Intervention

The Future of Aminoglycosides: The End or Renaissance?

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