Supramolecular Antagonists Promote Mitochondrial Dysfunction

Li, Mingming; Song, Yanqiu; Song, Na; Wu, Guangyao; Zhou, Hao; Long, Jiafu; Zhang, Pengcheng; Shi, Linqi; Yu, Zhilin

doi:10.1021/acs.nanolett.1c01469

Cited by 42 publications

(26 citation statements)

References 42 publications

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“…The precise self-assembly of peptides within living systems bestows in situ formation of biomaterials with great potential ranging from disease diagnosis to treatment. − While the formation of peptide nanostructures upon exposure to endogenous biomarkers gives rise to detectable signals for disease diagnosis, − self-assembly of peptides surrounding biological structures conventionally allows for regulation of intrinsic processes, thereby manipulating cell fate for therapeutic functions . The spatial distribution of the self-assembly of peptides within living systems could be in principle directed by incorporation of the moieties exhibiting the affinity with the corresponding biological structures, combining with the stimuli-responsive reactions occurred on peptides. − Thus far, a considerable number of peptide assembling systems targeting extracellular matrices, cellular surface, organelles, − or proteins , have been established and severed as a promising strategy for the development of new-generation theranostic agents. However, despite the progress achieved over the past decade, there remains a gap between the disease therapeutic efficacy of targeted peptide assemblies and clinical translation, thus demonstrating the necessity of developing advanced peptide assembling systems in living cells.…”

Section: Introductionmentioning

confidence: 99%

In Situ Self-Sorting Peptide Assemblies in Living Cells for Simultaneous Organelle Targeting

Liu

et al. 2022

J. Am. Chem. Soc.

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Self-sorting is a common phenomenon in eukaryotic cells and represents one of the versatile strategies for the formation of advanced functional materials; however, developing artificial self-sorting assemblies within living cells remains challenging. Here, we report on the GSHresponsive in situ self-sorting peptide assemblies within cancer cells for simultaneous organelle targeting to promote combinatorial organelle dysfunction and thereby cell death. The self-sorting system was created via the design of two peptides E3C16E6 and EVM SeO derived from lipidinspired peptide interdigitating amphiphiles and peptide bola-amphiphiles, respectively. The distinct organization patterns of the two peptides facilitate their GSH-induced self-sorting into isolated nanofibrils as a result of cleavage of disulfide-connected hydrophilic domains or reduction of selenoxide groups. The GSH-responsive in situ self-sorting in the peptide assemblies within HeLa cells was directly characterized by super-resolution structured illumination microscopy. Incorporation of the thiol and ER-targeting groups into the self-sorted assemblies endows their simultaneous targeting of endoplasmic reticulum and Golgi apparatus, thus leading to combinatorial organelle dysfunction and cell death. Our results demonstrate the establishment of the in situ self-sorting peptide assemblies within living cells, thus providing a unique platform for drug targeting delivery and an alternative strategy for modulating biological processes in the future.

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Section: Introductionmentioning

confidence: 99%

In Situ Self-Sorting Peptide Assemblies in Living Cells for Simultaneous Organelle Targeting

Liu

et al. 2022

J. Am. Chem. Soc.

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“…The intimate relationship between the structural features of peptide nanostructures and amino acid sequences has been thoroughly elucidated over the past few decades. − This has inspired establishment of various controllable self-assembling peptide systems based on stimuli-responsive reactions of natural or noncanonical amino acids, including redox-, − pH-, − photo-, and enzyme-responsive reactions, − and among others, , for creation of functional materials with great potential in disease diagnosis and treatment. − Among the internal or external stimuli, nitroreductase (NTR) is a flavin-containing enzyme conventionally overexpressed in the hypoxic region of solid tumors and enables one to reduce the nitro groups to (hydroxy)amino groups using NAD(P)H as the electron source . Thus far, a considerable number of NTR-responsive hydrogels, , imaging probes, − drug delivery vehicles, − or activatable prodrugs − have been developed and exhibit broad biomedical applications.…”

Section: Introductionmentioning

confidence: 99%

Noncanonical Amino Acids for Hypoxia-Responsive Peptide Self-Assembly and Fluorescence

Song

Cao

et al. 2021

J. Am. Chem. Soc.

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Design of endogenous stimuli-responsive amino acids allows for precisely modulating proteins or peptides under a biological microenvironment and thereby regulating their performance. Herein we report a noncanonical amino acid 2-nitroimidazol-1-yl alanine and explore its functions in creation of the nitroreductase (NTR)-responsive peptide-based supramolecular probes for efficient hypoxia imaging. On the basis of the reduction potential of the nitroimidazole unit, the amino acid was synthesized via the Mitsunobu reaction between 2-nitroimidazole and a serine derivate. We elucidated the relationship between the NTR-responsiveness of the amino acid and the structural feature of peptides involving a series of peptides. This eventually facilitates development of aromatic peptides undergoing NTR-responsive self-assembly by rationally optimizing the sequences. Due to the intrinsic role of 2-nitroimidazole in the fluorescence quench, we created a morphology-transformable supramolecular probe for imaging hypoxic tumor cells based on NTR reduction. We found that the resulting supramolecular probes penetrated into solid tumors, thus allowing for efficient fluorescence imaging of tumor cells in hypoxic regions. Our findings demonstrate development of a readily synthesized and versatile amino acid with exemplified properties in creating fluorescent peptide nanostructures responsive to a biological microenvironment, thus providing a powerful toolkit for synthetic biology and development of novel biomaterials.

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“…According to the manufacturer's protocol, a working solution of JC-1 staining was then prepared and added to cells for 15 min at 37 °C. Cells were then rinsed three times using a working buffer, followed by imaging with a flow cytometer [45]. 4.10.…”

Section: Characterization Of Fe-cur Ncpsmentioning

confidence: 99%

Ultrasmall Coordination Polymers for Alleviating ROS-Mediated Inflammatory and Realizing Neuroprotection against Parkinson’s Disease

Cheng

Liu

et al. 2022

Research

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Parkinson’s disease (PD) is the second most common neurodegenerative disease globally, and there is currently no effective treatment for this condition. Excessive accumulation of reactive oxygen species (ROS) and neuroinflammation are major contributors to PD pathogenesis. Herein, ultrasmall nanoscale coordination polymers (NCPs) coordinated by ferric ions and natural product curcumin (Cur) were exploited, showing efficient neuroprotection by scavenging excessive radicals and suppressing neuroinflammation. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD model, such ultrasmall Fe-Cur NCPs with prolonged blood circulation and BBB traversing capability could effectively alleviate oxidative stress, mitochondrial dysfunction, and inflammatory condition in the midbrain and striatum to reduce PD symptoms. Thus, this study puts forth a unique type of therapeutics-based NCPs that could be used for safe and efficient treatment of PD with potential in clinical translation.

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Supramolecular Antagonists Promote Mitochondrial Dysfunction

Cited by 42 publications

References 42 publications

In Situ Self-Sorting Peptide Assemblies in Living Cells for Simultaneous Organelle Targeting

In Situ Self-Sorting Peptide Assemblies in Living Cells for Simultaneous Organelle Targeting

Noncanonical Amino Acids for Hypoxia-Responsive Peptide Self-Assembly and Fluorescence

Ultrasmall Coordination Polymers for Alleviating ROS-Mediated Inflammatory and Realizing Neuroprotection against Parkinson’s Disease

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