Novel HIV Tat antagonists

Lapidot, Aviva; Litovchick, Alexander

doi:10.1002/1098-2299(200007/08)50:3/4<502::aid-ddr34>3.0.co;2-l

Cited by 11 publications

(13 citation statements)

References 137 publications

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“…At least in the case of TAR RNA, tetra-to hexaarginylated AACs binding pattern is in accordance with the peptide-like binding [10][11][12]19]. Based on our previous in vitro binding studies to TAR RNA and anti-HIV-1 activities of various arginine and guanidine derivatives of aminoglycosides, we proposed that the a-amino groups of the arginine moieties play an important role in TAR RNA site specific recognition and in anti-HIV-1 activity [15,17]. Thus, AACs bear features of both aminoglycosides and peptides.…”

Section: Binding Of Aminoglycoside-arginine Conjugates To Tar Andsupporting

confidence: 63%

Structure–activity relationships of aminoglycoside‐arginine conjugates that bind HIV‐1 RNAs as determined by fluorescence and NMR spectroscopy

et al. 2004

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We present here a new set of aminoglycoside-arginine conjugates (AACs) that are either site-specific or per-arginine conjugates of paromomycin, neamine, and neomycin B as well as their structure-activity relationships. Their binding constants (K D ) for TAR and RRE RNAs, measured by fluorescence anisotropy, revealed dependence on the number and location of arginines in the different aminoglycoside conjugates. The binding affinity of the per-arginine aminoglycosides to TAR is higher than to RRE, and hexa-arginine neomycin B is the most potent binder (K D = 5 and 23 nM, respectively). The 2D TOCSY NMR spectrum of the TAR monoarginine-neomycin complex reveals binding at the bulge region of TAR.

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Section: Binding Of Aminoglycoside-arginine Conjugates To Tar Andsupporting

confidence: 63%

Structure–activity relationships of aminoglycoside‐arginine conjugates that bind HIV‐1 RNAs as determined by fluorescence and NMR spectroscopy

et al. 2004

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“…To address this, we have examined the ability of a novel HIV‐1 transactivator of transcription (Tat) antagonist, the neomycin B hexa‐arginine conjugate NeoR (Fig. 1; Lapidot and Litovchick 2000; Lapidot et al . 2000; Litovchick et al .…”

mentioning

confidence: 99%

“…the tri‐arginine derivative of gentamicin (R3G) and the tetra‐arginine derivative of kanamycin (R4K), that have been designed and synthesized as HIV‐1 Tat antagonists (Litovchick et al . 1999, 2000, 2001; Lapidot and Litovchick 2000; Lapidot et al . 2000).…”

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confidence: 99%

The Tat antagonist neomycin B hexa‐arginine conjugate inhibits gp‐120‐induced death of human neuroblastoma cells

Catani

Corasaniti

Ranalli

et al. 2003

Journal of Neurochemistry

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Several patients with acquired immunodeficiency syndrome (AIDS) develop neurological complications, which are referred to as human immunodeficiency virus (HIV)-associated dementia (HAD). The HIV-1 coat glycoprotein gp-120 has been proposed as the major etiologic agent for neuronal loss reported postmortem in the brain of AIDS patients. Chemokine receptors may play a role in gp-120-triggered neurotoxicity, both in vitro and in vivo, thus being an intriguing target for developing therapeutic strategies aimed to prevent or reduce neuronal damage occurring during HIV infection. We have previously shown that human CHP100 neuroblastoma cells express CXCR4 and CCR5 chemokine receptors and that interaction between gp-120 and these receptors contributes to cytotoxicity elicited by the protein. Here, we examined the neuroprotective potential of neomycin B hexa-arginine conjugate (NeoR), a recently synthesized compound with anti-HIV activity. We found that gp-120-triggered death is significantly reduced by NeoR, and this protective effect seems related to the ability of NeoR to interact with CXCR4 receptors. The ability of NeoR to cross the blood-brain barrier, as demonstrated in mice by systemic administration of the fluorescein conjugate drug, makes this compound a powerful and attractive therapeutic agent.

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“…Different compounds have been evaluated as TAR binding molecules (8). Combinatorial approaches have been used to identify peptoids able to selectively recognize TAR and specifically inhibit the interaction of TAR with Tat in biochemical assays.…”

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confidence: 99%

Loop–loop interaction of HIV-1 TAR RNA with N3′ → P5′ deoxyphosphoramidate aptamers inhibits in vitro Tat-mediated transcription

Darfeuille

Arzumanov

Gryaznov

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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A hairpin RNA aptamer has been identified by in vitro selection against the transactivation-responsive element (TAR) of HIV-1. A nuclease-resistant N3 3 P5 phosphoramidate isosequential analog of this aptamer also folds as a hairpin and forms with TAR a loop-loop ''kissing'' complex with a binding constant in the low nanomolar range as demonstrated by electrophoretic mobilityshift assays and surface plasmon resonance experiments. The key structural determinants, which contribute to the stability of the RNA aptamer-TAR complex, loop complementarity and the GA residues closing the aptamer loop, remain crucial for the N3 3 P5 aptamer-TAR complex. Moreover, the N3 3 P5 phosphoramidate aptamer specifically interferes with the binding of a peptide derived from the transactivator protein (Tat) peptide to TAR and selectively inhibits the Tat-mediated transcription in an in vitro assay, which marks this nuclease-resistant aptamer as a relevant candidate for experiments in cells.

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Novel HIV Tat antagonists

Cited by 11 publications

References 137 publications

Structure–activity relationships of aminoglycoside‐arginine conjugates that bind HIV‐1 RNAs as determined by fluorescence and NMR spectroscopy

Structure–activity relationships of aminoglycoside‐arginine conjugates that bind HIV‐1 RNAs as determined by fluorescence and NMR spectroscopy

The Tat antagonist neomycin B hexa‐arginine conjugate inhibits gp‐120‐induced death of human neuroblastoma cells

Loop–loop interaction of HIV-1 TAR RNA with N3′ → P5′ deoxyphosphoramidate aptamers inhibits in vitro Tat-mediated transcription

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