Cell‐Penetrating, Dimeric α‐Helical Peptides: Nanomolar Inhibitors of HIV‐1 Transcription

Jang, Seok–Myeong; Hyun, Soonsil; Kim, Seoyeon; Lee, Seonju; Lee, Im Soon; Baba, Masanori; Lu, Yan; Yu, Jaehoon

doi:10.1002/ange.201404684

Cited by 16 publications

(10 citation statements)

References 31 publications

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“…Jang et al designed dimeric α-helical peptidyl inhibitors against the HIV Tat-TAR interaction. 336 They dimerized an amphipathic α-helical peptide consisting of leucine and lysine residues through a pair of disulfide bonds and the dimer, LK-4, showed potent binding to the TAR RNA sequence (K D = 0.059 nM) and robust cellular uptake (70−90% fluorescently positive cells at 10 nM concentration). Endocytosis was proposed as the predominant uptake mechanism at low concentrations (10 nM), as treatment with wortmannin, amiloride, or at 4 °C virtually eliminated uptake.…”

Section: Chemical Reviewsmentioning

confidence: 99%

Understanding Cell Penetration of Cyclic Peptides

2019

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Approximately 75% of all disease-relevant human proteins, including those involved in intracellular protein−protein interactions (PPIs), are undruggable with the current drug modalities (i.e., small molecules and biologics). Macrocyclic peptides provide a potential solution to these undruggable targets because their larger sizes (relative to conventional small molecules) endow them the capability of binding to flat PPI interfaces with antibody-like affinity and specificity. Powerful combinatorial library technologies have been developed to routinely identify cyclic peptides as potent, specific inhibitors against proteins including PPI targets. However, with the exception of a very small set of sequences, the vast majority of cyclic peptides are impermeable to the cell membrane, preventing their application against intracellular targets. This Review examines common structural features that render most cyclic peptides membrane impermeable, as well as the unique features that allow the minority of sequences to enter the cell interior by passive diffusion, endocytosis/endosomal escape, or other mechanisms. We also present the current state of knowledge about the molecular mechanisms of cell penetration, the various strategies for designing cell-permeable, biologically active cyclic peptides against intracellular targets, and the assay methods available to quantify their cell-permeability.

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Section: Chemical Reviewsmentioning

confidence: 99%

Understanding Cell Penetration of Cyclic Peptides

2019

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“…13,15 Recently, we discovered that LK-3, a bis-disulfide bridged dimer derivative of LKα14, is translocated into cells at nanomolar concentrations. 16,17 This finding stimulated us to explore the mechanistic underpinnings of cell penetration of these bundle peptides. Motivated by the others' earlier observations of LKα14 14,15 and our results of cell penetrability of LK-3, here in this report, we carried out the current investigation aimed at elucidating the details of structural characteristics leading the interactions between helical bundles that promote nanosized oligomer formation (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 99%

Oligomer Formation Propensities of Dimeric Bundle Peptides Correlate with Cell Penetration Abilities

et al. 2018

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LK-3, an amphipathic dimeric peptide linked by two disulfide bonds, and related isomeric bundles were synthesized, and their cell penetrating abilities were investigated. The measurements using size exclusion chromatography and dynamic light scattering show that LK-3 and its isomers form cell penetrating oligomers. Calculations, performed for various types of peptide isomers, elucidate a strong correlation between the amphipathic character of dimers and cell penetration ability. The results suggest that the amphipathicities of LK-3 and related bundle dimers are responsible for their oligomerization propensities which in turn determine their cell penetrating abilities. The observations made in this study provide detailed information about the mechanism of cell uptake of LK-3 and suggest a plausible insight of the early stage of nanoparticle formation of the cell penetrating amphipathic peptides.

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“…CPPs-mediated cellular internalization is an energy-dependent cell process, such as endocytosis or receptor-mediated uptake [ 80 , 81 ]. Although CPPs can enhance the in vitro and in vivo efficacy of impenetrable molecules in biomedical applications, it still has the limitations of low osmotic concentration and poor target selectivity [ 82 , 83 , 84 , 85 ]. Furthermore, cationic CPPs present problems, such as their inability to selectively home to the target.…”

Section: Categories Of Drug Conjugatesmentioning

confidence: 99%

Research Progress of Conjugated Nanomedicine for Cancer Treatment

Zhao

Chen

Hong³

et al. 2022

Pharmaceutics

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The conventional cancer therapeutic modalities include surgery, chemotherapy and radiotherapy. Although immunotherapy and targeted therapy are also widely used in cancer treatment, chemotherapy remains the cornerstone of tumor treatment. With the rapid development of nanotechnology, nanomedicine is believed to be an emerging field to further improve the efficacy of chemotherapy. Until now, there are more than 17 kinds of nanomedicine for cancer therapy approved globally. Thereinto, conjugated nanomedicine, as an important type of nanomedicine, can not only possess the targeted delivery of chemotherapeutics with great precision but also achieve controlled drug release to avoid adverse effects. Meanwhile, conjugated nanomedicine provides the platform for combining several different therapeutic approaches (chemotherapy, photothermal therapy, photodynamic therapy, thermodynamic therapy, immunotherapy, etc.) with the purpose of achieving synergistic effects during cancer treatment. Therefore, this review focuses on conjugated nanomedicine and its various applications in synergistic chemotherapy. Additionally, the further perspectives and challenges of the conjugated nanomedicine are also addressed, which clarifies the design direction of a new generation of conjugated nanomedicine and facilitates the translation of them from the bench to the bedside.

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Cell‐Penetrating, Dimeric α‐Helical Peptides: Nanomolar Inhibitors of HIV‐1 Transcription

Cited by 16 publications

References 31 publications

Understanding Cell Penetration of Cyclic Peptides

Understanding Cell Penetration of Cyclic Peptides

Oligomer Formation Propensities of Dimeric Bundle Peptides Correlate with Cell Penetration Abilities

Research Progress of Conjugated Nanomedicine for Cancer Treatment

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