Inhibition of HIV-1 Replication by a Tat RNA-Binding Domain Peptide Analog

Choudhury, Indrani; Wang, Jihong; Rabson, Arnold B.; Stein, Steven; Pooyan, Shahriar; Stein, Stanley J.; Leibowitz, Michael J.

doi:10.1097/00042560-199802010-00002

Cited by 31 publications

(33 citation statements)

References 40 publications

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“…The Tat protein is a key regulatory protein of HIV-1, and thus inhibition of its function is of therapeutic potential. Inhibition of Tat activity has been extensively researched and several families of small molecules that inhibit Tat activity via inhibition of the Tat-TAR binding have been reported (37)(38)(39)(40)(41). Our results indeed show (Fig.…”

Section: Screening Of the Arm Mimetic Library For Inhibition Of Nuclesupporting

confidence: 80%

Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif

Friedler¹,

Friedler²,

Luedtke³

et al. 2000

Journal of Biological Chemistry

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We have used the backbone cyclic proteinomimetics approach to develop peptides that functionally mimic the arginine-rich motif (ARM) of the HIV-1 Tat protein. This consensus sequence serves both as a nuclear localization signal (NLS) and as an RNA binding domain. Based on the NMR structure of Tat, we have designed and synthesized a backbone cyclic ARM mimetic peptide library. The peptides were screened for their ability to mediate nuclear import of the corresponding BSA conjugates in permeabilized cells. One peptide, designated "Tat11," displayed active NLS properties. Nuclear import of Tat11-BSA was found to proceed by the same distinct pathway used by the Tat-NLS and not by the common importin ␣ pathway, which is used by the SV40-NLS. Most of the Tat-derived backbone cyclic peptides display selective inhibitory activity as demonstrated by the inhibition of the nuclear import mediated by the Tat-NLS and not by the SV40-NLS. The Tat-ARM-derived peptides, including Tat-11, also inhibited binding of the HIV-1 Rev-ARM to its corresponding RNA element (Rev response element) with inhibition constants of 5 nM. Here we have shown for the first time (a) a functional mimetic of a protein sequence, which activates a nuclear import receptor and (b) a mimetic of a protein sequence with a dual functionality. Tat11 is a lead compound which can potentially inhibit the HIV-1 life cycle by a dual mechanism: inhibition of nuclear import and of RNA binding.Proteinomimetics are small molecules that can mimic the structure and/or function of active sites within proteins (1). They are useful for detailed study of protein folding, structure, and function. The major potential application of proteinomimetics is, however, therapeutic; such molecules can be used to block protein-protein and/or protein-nucleic acid interactions, thus interfering with undesired biological processes (2-4). Being relatively small, proteinomimetics often solve acute problems associated with the use of proteins as drugs, such as antigenicity, low bioavailability, high cost, and rapid enzymatic degradation.Two properties of the parent protein must be retained when designing proteinomimetics: (i) the bioactive conformation of the desired active site and (ii) a certain degree of conformational flexibility to allow induced fit. Linear peptides are not optimal candidates to mimic proteins, because they equilibrate between multiple conformations and thus adaptation of the bioactive conformation is at an entropic cost. Introduction of conformational constraints into the peptide is thus needed to generate a proteinomimetic. Being relatively small and conformationally constrained, cyclic peptides are excellent candidates to serve as proteinomimetics. Backbone cyclization of peptides is the method of cyclization developed and used in our lab. It results in peptides with improved selectivity, enhanced metabolic stability, and high bioavailability (5-9). To select the most active backbone cyclic (BC) 1 peptide based on a given sequence, we have developed the "cycloscan" ...

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Section: Screening Of the Arm Mimetic Library For Inhibition Of Nuclesupporting

confidence: 80%

Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif

Friedler¹,

Friedler²,

Luedtke³

et al. 2000

Journal of Biological Chemistry

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“…In a first set of experiments, the virus was added simultaneously with the peptides. The reference inhibitor, Tat peptide 11, [15] is characterized by an IC 50 value of 20 mm. d-Arg-dArg-d-Arg shows only weak effects (IC 50 = 500 mm), probably due to promiscuous binding to all kinds of polyanions.…”

Section: Resultsmentioning

confidence: 99%

Tripeptides from Synthetic Amino Acids Block the Tat–TAR Association and Slow Down HIV Spread in Cell Cultures

Ludwig¹,

Krebs²,

Stoll³

et al. 2007

ChemBioChem

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Non-natural amino acids with aromatic or heteroaromatic side chains were incorporated into tripeptides of the general structure Arg-X-Arg and tested as ligands of the HIV RNA element TAR. Some of these compounds could compete efficiently with the association of TAR and Tat and downregulated a TAR-controlled reporter gene in HeLa cells. Peptide 7, which contains a 2-pyrimidinyl-alkyl chain, also inhibited the spread of HIV-1 in cell cultures. NMR studies of 7 bound to HIV-2-TAR gave evidence for contacts in the bulge region.

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“…We have previously studied small peptides that bind specifically to RNA regulatory elements, with binding depending on RNA structure (Wang et al, 1995;Choudhury et al, 1998Choudhury et al, , 1999. To develop the binding element of the bifunctional agent, one approach has been to prepare small libraries conformationally constrained cyclic peptides were prepared on SPOTs membranes, to determine which peptide has optimized specificity of binding to the 5'-UTR of HER-2/neu mRNA.…”

Section: Creation Of a Peptide Through Combinatorial Synthesis That Bmentioning

confidence: 99%

Dual-Specificity Anti-HER-2/neu Antisense DNA Agents for Breast Cancer Therapy

Stein¹

2000

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Inhibition of HIV-1 Replication by a Tat RNA-Binding Domain Peptide Analog

Cited by 31 publications

References 40 publications

Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif

Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif

Tripeptides from Synthetic Amino Acids Block the Tat–TAR Association and Slow Down HIV Spread in Cell Cultures

Dual-Specificity Anti-HER-2/neu Antisense DNA Agents for Breast Cancer Therapy

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