RNA Grooves Can Accommodate Disulfide‐Bridged Bundles of α‐Helical Peptides

Hyun, Soonsil; Na, Ji-Young; Lee, Su Jin; Park, Sangeun; Yu, Jaehoon

doi:10.1002/cbic.201000072

Cited by 15 publications

(20 citation statements)

References 53 publications

(36 reference statements)

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“…We have recently discovered that the penetrating concentration of a 16‐meric amphipathic α‐helical peptide (LKKLCKLLKKLCKLAG; leucine (L) and lysine (K)‐rich α‐helical (LK) peptide) could be greatly reduced by dimerization between two LK‐peptide molecules through the oxidative formation of two disulfide bonds 15. Remarkably, the dimeric peptide with an antiparallel structure as the major form can penetrate cells and inhibit the RNA transcription of HIV genes at nanomolar concentrations over 100‐fold lower than to the penetrating concentrations of other conventional CPPs such as Tat or oligoarginines.…”

Section: Resultsmentioning

confidence: 99%

Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations

Chong

Nam

et al. 2018

Advanced Science

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An amphipathic leucine (L) and lysine (K)‐rich α‐helical peptide is multimerized based on helix‐loop‐helix structures to maximize the penetrating activities. The multimeric LK‐based cell penetrating peptides (LK‐CPPs) can penetrate cells as protein‐fused forms at 100–1000‐fold lower concentrations than Tat peptide. The enhanced penetrating activity is increased through multimerization by degrees up to the tetramer level. The multimeric LK‐CPPs show rapid cell penetration through macropinocytosis at low nanomolar concentrations, unlike the monomeric LK, which have slower penetrating kinetics at much higher concentrations. The heparan sulfate proteoglycan (HSPG) receptors are highly involved in the rapid internalization of multimeric LK‐CPPs. As a proof of concept of biomedical applications, an adipogenic transcription factor, peroxisome proliferator‐activated receptor gamma 2 (PPAR‐γ 2), is delivered into preadipocytes, and highly enhanced expression of adipogenic genes at nanomolar concentrations is induced. The multimeric CPPs can be a useful platform for the intracellular delivery of bio‐macromolecular reagents that have difficulty with penetration in order to control biological reactions in cells at feasible concentrations for biomedical purposes.

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Section: Resultsmentioning

confidence: 99%

Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations

Chong

Nam

et al. 2018

Advanced Science

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“…16b, 18 Another method is to perform a high-throughput screen using chemical libraries, in which a large number of diverse ligands can be screened against various RNAs with rapid turnover of results. 19 Several RNAs have been well-studied as therapeutic targets, including viral RNAs such as the HIV-1 dimerization initiation site (DIS) 20 and the HCV internal ribosome entry site (IRES), 21 as well as expanded nucleotide repeats r(CCUG) involved with the development of myotonic dystrophy type 2. 22 Herein, we focus on the review of medium-sized peptides and peptidomimetics used in targeting two conserved RNA structures of HIV-1: the transactivation response element (TAR) and rev response element (RRE) RNA, as well as the utilization of branched peptide scaffolds in therapeutics and our contribution in this field.…”

Section: Recognition Of Rna As a Therapeutic Targetmentioning

confidence: 99%

“…Through an alanine scan using 1 as a lead peptide, sequences 10 and 11 were found to improve binding affinities towards RRE, with each showing selectivity against TAR RNA. 21a Yu and co-workers also developed constrained peptides from 1 in which the 5 th and 12 th Leu residues were replaced with Cys and then cross-linked by various maleimido derivatives. 21b Unfortunately, none of the peptides showed increased binding affinity towards RRE in relation to 1 , with K d s ranging from 46 to 90 nM.…”

Section: Hiv-1 Rre Rna As a Therapeutic Targetmentioning

confidence: 99%

“…21a Yu and co-workers also developed constrained peptides from 1 in which the 5 th and 12 th Leu residues were replaced with Cys and then cross-linked by various maleimido derivatives. 21b Unfortunately, none of the peptides showed increased binding affinity towards RRE in relation to 1 , with K d s ranging from 46 to 90 nM. K d s in the picomolar range were achieved through the covalent crosslinking of the peptides through intermolecular disulfide bonds; however, these peptides did not display selectivity for RRE or TAR RNA.…”

Section: Hiv-1 Rre Rna As a Therapeutic Targetmentioning

confidence: 99%

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HIV-1 drug discovery: targeting folded RNA structures with branched peptides

Wynn

Santos

2015

Org. Biomol. Chem.

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Human immunodeficiency virus type 1 (HIV-1) is an RNA virus that is prone to high rates of mutation. While the disease is managed with current antiretroviral therapies, drugs with a new mode of action are needed. A strategy towards this goal is aimed at targeting the native three-dimensional fold of conserved RNA structures. This perspective highlights medium-sized peptides and peptidomimetics used to target two conserved RNA structures of HIV-1. In particular, branched peptides have the capacity to bind in a multivalent fashion, utilizing a large surface area to achieve the necessary affinity and selectivity toward the target RNA.

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“…11 Several RNAs have been well-studied as therapeutic targets, including expanded nucleotide repeats r(CCUG) involved with the development of myotonic dystrophy type 2, 12–15 as well as viral RNAs that contain targets such as the HIV-1 dimerization initiation site (DIS) 16–19 and the HCV internal ribosome entry site (IRES). 20, 21 The Rev/Rev Response Element (RRE) pathway has become a high profile drug target due to its critical role in the proliferation of HIV-1. 22 RRE is a highly conserved region in the HIV-1 genome that spans approximately 351 nucleotides in the env gene.…”

Section: Introductionmentioning

confidence: 99%

Characterization and in vitro activity of a branched peptide boronic acid that interacts with HIV-1 RRE RNA

Wynn

Zhang

Tebit

et al. 2016

Bioorganic & Medicinal Chemistry

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A branched peptide containing multiple boronic acids was found to bind RRE IIB selectively and inhibit HIV-1 p24 capsid production in a dose-dependent manner. Structure-activity relationship studies revealed that branching in the peptide is crucial for the low micromolar binding towards RRE IIB, and that the peptide demonstrates selectivity towards RRE IIB in the presence of tRNA. Footprinting studies suggest a binding site on the upper stem and internal loop region of the RNA, which induces enzymatic cleavage of the internal loops of RRE IIB upon binding.

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RNA Grooves Can Accommodate Disulfide‐Bridged Bundles of α‐Helical Peptides

Cited by 15 publications

References 53 publications

Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations

Multimeric Amphipathic α‐Helical Sequences for Rapid and Efficient Intracellular Protein Transport at Nanomolar Concentrations

HIV-1 drug discovery: targeting folded RNA structures with branched peptides

Characterization and in vitro activity of a branched peptide boronic acid that interacts with HIV-1 RRE RNA

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