Enzymatic Cleavage of Branched Peptides for Targeting Mitochondria

He, Hongjian; Wang, Jiaqing; Wang, Huaimin; Zhou, Ning; Yang, Daejong; Green, Douglas R.; Xu, Bing

doi:10.1021/jacs.7b11582

Cited by 152 publications

(138 citation statements)

References 37 publications

(38 reference statements)

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“…In addition to the above‐mentioned phosphatase‐triggered self‐assembly, other enzymes (including furin, caspase, carboxylesterase, esterase, MMP, transglutaminase, and enterokinase) and endogenous small molecules can also initiate supramolecular self‐assembly in biological environments, which has been well documented . Here, we discuss the tandem enzymatic and chemical reactions to initiate self‐assembly, which could show superior selectivity against cancer cells.…”

Section: Construction Of Eisa In Cancer Cellsmentioning

confidence: 96%

Enzyme‐Instructed Supramolecular Self‐Assembly with Anticancer Activity

et al. 2018

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Cancer remains one of the leading causes of death, which has continuously stimulated the development of numerous functional biomaterials with anticancer activities. Herein is reviewed one recent trend of biomaterials focusing on the advances in enzyme‐instructed supramolecular self‐assembly (EISA) with anticancer activity. EISA relies on enzymatic transformations to convert designed small‐molecular precursors into corresponding amphiphilic residues that can form assemblies in living systems. EISA has shown some advantages in controlling cell fate from three aspects. 1) Based on the abnormal activity of specific enzymes, EISA can differentiate cancer cells from normal cells. In contrast to the classical ligand–receptor recognition, the targeting capability of EISA relies on dynamic control of the self‐assembly process. 2) The interactions between EISA and cellular components directly disrupt cellular processes or pathways, resulting in cell death phenotypes. 3) EISA spatiotemporally controls the distribution of therapeutic agents, which boosts drug delivery efficiency. Therefore, with regard to the development of EISA, the aim is to provide a perspective on the future directions of research into EISA as anticancer theranostics.

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Section: Construction Of Eisa In Cancer Cellsmentioning

confidence: 96%

Enzyme‐Instructed Supramolecular Self‐Assembly with Anticancer Activity

et al. 2018

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“…The FLAG-tag precursor delivers cargo to the mitochondria, as evidenced by the delivery of DOX or RPE (R-phycoerythrin). The branched peptide precursor decreases the IC 50 of DOX from 3.0 to 400 nM [76].…”

Section: In Situ Nanostructures Inside Mitochondria For Cancer Therapymentioning

confidence: 96%

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

Jeena

Kim

Jin

et al. 2019

Cancers

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The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches.In healthy cells, mitochondria execute a controlled regulation of multiple functions to maintain the cellular growth-death cycle. However, in the case of tumor cells, to meet the higher metabolic demand of rapidly proliferating cells, dysregulation of mitochondrial metabolism occurs [14,15]. The difference between cancer cell mitochondria and normal cells includes several functional alterations, such as mutation of mtDNA that lead to OXPHOS (oxidative phosphorylation) inhibition and thus deficient respiration and ATP generation, mutation of mtDNA-encoded mitochondrial enzymes, such as SDH (succinate dehydrogenase), IDH1 (isocitrate dehydrogenase 1), IDH2 (isocitrate dehydrogenase 2) [16], and structural differences, such as higher membrane potential of cancer cell mitochondria and higher basicity inside the mitochondrial lumen. The evasion of cell death or inhibition of mitochondria-mediated apoptosis is a hallmark for cancer. Mitochondria generate ROS, which is necessary for signaling under normal conditions. However, when apoptosis is inhibited in the case of cancer, ROS contributes to the neoplastic transformation. Furthermore, for supporting tumor cell survival under harsh tumorigenic conditions, such as nutrient depletion and hypoxia, mitochondria provide flexibility in several pathways either by up-or downregulation [17]. This altered mitochondrial metabolism of cancer cells compared with that of their normal counterparts is advantageous for the selective targeting of cancer mitochondria in therapeutics, which focuses on the cancer mitochondria specific features [18]. Directing the therapeutic agent to the mitochondria is an efficient way of eliminating cancer cells because the designed drug molecules could act at the central point of the cell, and therefore, engineering mitochondrial-targeted therapeutic agents have gained much interest in cancer thera...

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“…Unlike the commonly used mitochondria‐targeting molecules (lipophilic and cationic), which may cause undesired cytotoxicity, a branched peptide with negative charge is able to target mitochondria via instructed assembly on mitochondria . 11 consists of a well‐established protein tag (i.e., FLAG‐tag) and a self‐assembling motif, and acts as the substrate of enterokinase (ENTK).…”

Section: Peptide Assemblies In the Cellular Environment And Applicationsmentioning

confidence: 99%

Assemblies of Peptides in a Complex Environment and their Applications

Wang

Feng

2019

Angewandte Chemie

Self Cite

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Using peptide assemblies with emergent properties to achieve elaborate functions has attracted increasing attention in recent years. Besides tailoring the self‐assembly of peptides in vitro, peptide research is advancing into a new and exciting frontier: the rational design of peptide assemblies (or their derivatives) for biological functions in a complex environment. This Minireview highlights recent developments in peptide assemblies and their applications in biological systems. After introducing the unique merits of peptide assemblies, we discuss the recent progress in designing peptides (or peptide derivatives) for self‐assembly with conformational control. Then, we describe biological functions of peptide assemblies, with an emphasis on approach‐instructed assembly for spatiotemporal control of peptide assemblies, in the cellular context. Finally, we discuss the future promises and challenges of this exciting area of chemistry.

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Enzymatic Cleavage of Branched Peptides for Targeting Mitochondria

Cited by 152 publications

References 37 publications

Enzyme‐Instructed Supramolecular Self‐Assembly with Anticancer Activity

Enzyme‐Instructed Supramolecular Self‐Assembly with Anticancer Activity

Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy

Assemblies of Peptides in a Complex Environment and their Applications

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