Design of β‐Hairpin Peptidomimetics That Inhibit Binding of α‐Helical HIV‐1 Rev Protein to the Rev Response Element RNA

Moehle, Kerstin; Athanassiou, Zafiria; Patora, Krystyna; Davidson, Amy; Varani, Gabriele; Robinson, John A.

doi:10.1002/anie.200702801

Cited by 51 publications

(44 citation statements)

References 19 publications

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“…Members of this series showed antiviral activity in human lymphocytes from clinical isolates that was slightly weaker than the antiviral drug nevirapine [28]. A similar strategy identified inhibitors for another major HIV protein-RNA complex, which bind to the RRE RNA [87]. The TAR binding peptide provided high quality NMR data [28], enabling a structure determination that has shed light on earlier studies of small molecules binding to TAR [29,30], as well as the binding of the native protein.…”

Section: Strategies For Identifying Rna-binding Ligandsmentioning

confidence: 95%

Strategies for the Design of Rna-Binding Small Molecules

Aboul‐ela

2009

Future Med. Chem.

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Bacterial ribosomal RNA is the target of clinically important antibiotics, while biologically important RNAs in viral and eukaryotic genomes present a range of potential drug targets. The physicochemical properties of RNA present difficulties for medicinal chemistry, particularly when oral availability is needed. Peptidic ligands and analysis of their RNA-binding properties are providing insight into RNA recognition. RNA-binding ligands include far more chemical classes than just aminoglycosides. Chemical functionalities from known RNA-binding small molecules are being exploited in fragment- and ligand-based projects. While targeting of RNA for drug design is very challenging, continuing advances in our understanding of the principles of RNA-ligand interaction will be necessary to realize the full potential of this class of targets.

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Section: Strategies For Identifying Rna-binding Ligandsmentioning

confidence: 95%

Strategies for the Design of Rna-Binding Small Molecules

Aboul‐ela

2009

Future Med. Chem.

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“…12 However, these approaches are labor intensive and often low yielding. In cases where a library of cyclic peptides is warranted, as in Robinson’s approach to disrupting protein-RNA and protein-protein interactions with cyclic β-hairpins, 13 an alternate method of cyclization would be advantageous.…”

Section: Introductionmentioning

confidence: 99%

Positional effects of click cyclization on β-hairpin structure, stability, and function

Park

Waters

2013

Org. Biomol. Chem.

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The use of the copper (I)-assisted azide-alkyne cycloaddition (CuAAC, or “click” reaction) as a method of β-hairpin stabilization was investigated at several different positions to determine the impact on hairpin structure and function, including hydrogen bonded sites, non-hydrogen bonded sites, and at the peptide termini. The role of the turn sequence in the peptide and the chain length of the azied were also investigated. It was determined that the CuAAC reaction was a suitable method for locking in β-hairpin structure in peptides possessing either the type I’ turn, VNGO and the type II’ turn, VpGO. Moreover, all cyclic variants exhibited improved thermal stability and resistance to proteolysis as compared to the non-cyclic peptides, regardless of the position in the strand. Additionally, the function of the CuAAC cyclized peptides was not altered as exhibited by similar binding affinities for ATP as the WKWK peptide. These studies provided a comprehensive method for CuAAC cyclization of β-hairpin peptides, which could further be utilized in the inhibition of protein-protein and protein-nucleic acid interactions.

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“…Structure-aided design has also proven useful for the design of small molecules that mimic the binding of proteins to RNA. For example, various peptidomimetics have been designed to target the HIV trans-activation response element (HIV TAR), providing compounds that are bioactive in cell culture (69–74). Another important approach is docking of small molecules into RNA dynamic ensembles generated using a combination of NMR spectroscopy and molecular dynamics simulations (75, 76).…”

Section: Development Of Strategies To Design Small Molecules To Targementioning

confidence: 99%

Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells

Childs‐Disney

Disney

2016

Annu. Rev. Pharmacol. Toxicol.

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RNA has become an increasingly important target for therapeutic interventions and for chemical probes that dissect and manipulate its cellular function. Emerging targets include human RNAs that have been shown to directly cause cancer, metabolic disorders, and genetic disease. In this review, we describe various routes to obtain bioactive compounds that target RNA, with a particular emphasis on the development of small molecules. We use these cases to describe approaches that are being developed for target validation, which include target-directed cleavage, classic pull-down experiments, and covalent cross-linking. Thus, tools are available to design small molecules to target RNA and to identify the cellular RNAs that are their targets.

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Design of β‐Hairpin Peptidomimetics That Inhibit Binding of α‐Helical HIV‐1 Rev Protein to the Rev Response Element RNA

Cited by 51 publications

References 19 publications

Strategies for the Design of Rna-Binding Small Molecules

Strategies for the Design of Rna-Binding Small Molecules

Positional effects of click cyclization on β-hairpin structure, stability, and function

Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells

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