Structure-tuned membrane active Ir-complexed oligoarginine overcomes cancer cell drug resistance and triggers immune responses in mice

Ji, Shuangshuang; Yang, Xiuzhu; Chen, Xiaolong; Li, Ang; Yan, Doudou; Xu, Haiyan; Fei, Hao

doi:10.1039/d0sc03975f

Cited by 23 publications

(23 citation statements)

References 74 publications

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“…This study reflects our continued efforts focusing on the precise regulation of hydrophobicity of CAPs for cargo delivery or cancer therapy (27,54), given that hydrophobicity is regarded as the most important determinant affecting CAPs' membrane activity (18,19,52,53). We hypothesized that the two functionalities dictated by the hydrophobicity of a CAP, i.e., membrane association and membrane lysis, can be separately tuned in one peptide sequence.…”

Section: Discussionmentioning

confidence: 88%

Hydrophobicity-tuned anion responsiveness underlies endosomolytic cargo delivery mediated by amphipathic vehicle peptides

Chen

Liu

et al. 2021

Journal of Biological Chemistry

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Peptide conformation can change subject to environment cues. This concept also applies to many cationic amphipathic peptides (CAPs) known to have cell membrane lytic or penetrative activities. Well-conditioned CAPs can match the properties of the target membrane to support their intended biological functions, e.g. , intracellular cargo delivery; however, the intricacy in such conditioning surpasses our current understanding. Here we focused on hydrophobicity, a key biophysical property that dictates the membrane activity of CAPs, and applied a structure–function strategy to evolve a template peptide for endosomolytic cargo delivery. The template was subjected to iterative adjustment to balance hydrophobicity between its N-terminal linear and C-terminal helical domains. We demonstrate that the obtained peptide, LP6, could dramatically promote cargo cell entry and facilitate cytosolic delivery of biomacromolecules such as FITC-dextran, saporin, and human IgG. Among the evolved peptide series, LP6 has low cytotoxicity and moderate hydrophobicity, exhibits maximum change in helical conformation in response to negatively charged phospholipids, and also shows an apparent aggregational behavior in response to sialic acid enrichment. These attributes of LP6 collectively indicate that its anion-responsive conformational change is a critical underlining of its endosomolytic cargo delivery capability. Our results also suggest that modulation of hydrophobicity serves as a key to the precise tuning of CAP's membrane activity for future biomedical applications.

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Section: Discussionmentioning

confidence: 88%

Hydrophobicity-tuned anion responsiveness underlies endosomolytic cargo delivery mediated by amphipathic vehicle peptides

Chen

Liu

et al. 2021

Journal of Biological Chemistry

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“…For luminescent staple linkers, Fei et al. have reported a luminogenic peptide stapling strategy utilizing bis(histidine)–iridium(III) complex coordination chemistry with RGD and oligoarginine peptides for cancer cell targeting, imaging and killing [18, 19] . Perrin et al.…”

Section: Figurementioning

confidence: 99%

“…have reported a luminogenic peptide stapling strategy utilizing bis(histidine)–iridium(III) complex coordination chemistry with RGD and oligoarginine peptides for cancer cell targeting, imaging and killing. [ 18 , 19 ] Perrin et al. have realized a mild, metal‐free, and late‐stage fluorescent isoindole crosslink strategy by employing phthalaldehyde‐mediated “isoindole intramolecular stapling” chemoselectively with peptides’ amine‐thiol groups, where the isoindole can serve as a fluorophore.…”

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confidence: 99%

Solid‐Phase Peptide Macrocyclization and Multifunctionalization via Dipyrrin Construction

Chau

Thor

et al. 2021

Angew Chem Int Ed

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We introduce a new and highly efficient synthetic protocol towards multifunctional fluorescent cyclopeptides by solid‐phase peptide macrocyclization via dipyrrin construction, with full scope of proteinogenic amino acids and different ring sizes. Various bicyclic peptides can be created by dipyrrin‐based crosslinking and double dipyrrin‐ring formation. The embedded dipyrrin can be either transformed to fluorescent BODIPY and then utilized as cancer‐selective targeted protein imaging probe in vitro, or directly employed as a selective metal sensor in aqueous media. This work provides a valuable addition to the peptide macrocyclization toolbox, and a blueprint for the development of multifunctional dipyrrin linkers in cyclopeptides for a wide range of potential bioapplications.

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“…Thee xcellent anti-tumor activity and precise subcellular localization of Ir III complexes have been well reported, [33] but until now none have been found to cause ICD.Encouragingly, immune responses and cancer cell death triggered by membrane-active iridium(III) complexed oligarginine peptides were reported recently by the Feig roup,s howing the potential of Ir III compounds in immunotherapeutic treatments.H owever,t his eruptive mode of cell death was based on the maturation of dendritic cells and the accumulation of inflammatory factors,i nstead of specific T-cell immune responses as in ICD. [34] Based on the idea that subcellular localization determines how the drug initially interacts with tumor cells, [35] and the groups experience in the design of organelle-targeted anticancer complexes, [36] the synthesis of two Ir III complexes which selectively accumulate in the ER is herein reported. Inspired by the ICD-inducing drug cyclophosphamide,abis(2-chloroethyl)-azane moiety was added to complex Ir1 only,w ith Ir2 as the reference compound.…”

Section: Introductionmentioning

confidence: 99%

An ER‐Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non‐Small‐Cell Lung Cancer

et al. 2021

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Immunogenic cell death (ICD) is a vital component of therapeutically induced anti‐tumor immunity. An iridium(III) complex (Ir1), containing an N,N‐bis(2‐chloroethyl)‐azane derivate, as an endoplasmic reticulum‐localized ICD inducer for non‐small cell lung cancer (NSCLC) is reported. The characteristic discharge of damage‐associated molecular patterns (DAMPs), that is, cell surface exposure of calreticulin (CRT), extracellular exclusion of high mobility group box 1 (HMGB1), and ATP, were generated by Ir1 in A549 lung cancer cells, accompanied by an increase in endoplasmic reticulum stress and reactive oxygen species (ROS). The vaccination of immunocompetent mice with Ir1‐treated dying cells elicited an antitumor CD8+ T cell response and Foxp3+ T cell depletion, which eventually resulted in long‐acting anti‐tumor immunity by the activation of ICD in lung cancer cells. Ir1 is the first Ir‐based complex that is capable of developing an immunomodulatory response by immunogenic cell death.

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Structure-tuned membrane active Ir-complexed oligoarginine overcomes cancer cell drug resistance and triggers immune responses in mice

Abstract: Structure optimized Ir-complexed cyclic octa-arginine shows a potential of “one-drug two-effects” for cancer treatment.

Cited by 23 publications

References 74 publications

Hydrophobicity-tuned anion responsiveness underlies endosomolytic cargo delivery mediated by amphipathic vehicle peptides

Hydrophobicity-tuned anion responsiveness underlies endosomolytic cargo delivery mediated by amphipathic vehicle peptides

Solid‐Phase Peptide Macrocyclization and Multifunctionalization via Dipyrrin Construction

An ER‐Targeting Iridium(III) Complex That Induces Immunogenic Cell Death in Non‐Small‐Cell Lung Cancer

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