A short peptide synthon for liquid–liquid phase separation

Abbas, Manzar; Lipiński, Wojciech P.; Nakashima, Karina K.; Huck, Wilhelm T. S.; Spruijt, Evan

doi:10.1038/s41557-021-00788-x

Cited by 166 publications

(227 citation statements)

References 64 publications

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“…[113] The lab of Spruijt has recently reported coacervate microdroplets made of even smaller peptidic-based units. [114] They designed dipeptides from the hydrophobic amino acids phenylalanine (Phe) and leucine (Leu), which they joined together through the hydrophilic, disulfide-containing cystamine linker. The formation of micrometer size droplets was achieved by shifting the pH from 5À6 to 7.…”

Section: Artificial Polypeptide-based Simple Coacervatesmentioning

confidence: 99%

Protein‐Based Encapsulation Strategies: Toward Micro‐ and Nanoscale Carriers with Increased Functionality

et al. 2022

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The word "capsule" derives from the Latin word "capsula," which can be translated to "small box" or "container." In pharmacy, this term was adopted as early as the 19th century when physicians were facing a serious problem: they had medication that would improve the lives of patients, but due to their awful taste and texture, most people were refusing to go through with their treatment. In France, the oleoresin of copaiba (that possesses a nauseating taste) was prescribed to people suffering from venereal disease, whose incidence skyrocketed as a result of the Napoleonic wars and the associated social unrest. To solve this problem, in 1834 Mothes and Dublanc came up with the first capsules made of gelatin that masked the taste and smell of the encapsulated drugs, thus allowing a more pleasant consumption. [1] Since then, encapsulation techniques have been widespread thanks to their numerous applications in protecting and delivering active ingredients such as drugs, [2] cosmetics, [3] fragrances, [4] agricultural substances, [5] and chemical reagents. [6] In addition to the taste-masking functions mentioned above, encapsulation strategies are useful to extend the shelf life of the (captured) substances, to protect them from the surrounding environment, and in some cases to transport and release them at specific sites. [7] Capsules' sizes can go from a few centimeters, like the ones developed by Mothes and Dublanc, to only a few tenths of nm depending on the desired application. [8] When capsule size ranges from 0.1 to 100 μm, they are designated as microcapsules and if the size is in the 1À100 nm range, they are called nanocapsules (IUPAC definition). [9] Microcapsules possess a larger inner volume than nanocapsules, which enables the loading of a higher amount of molecules of interest. In addition, thanks to their fragility, microcapsules can be easily broken by friction forces, which is highly desirable for applications such as cosmetics, flavor release, or textiles. [3,10,11] In contrast, nanocapsules have very small sizes, can pass (biological) barriers, and deliver their cargos with enhanced precision compared to free therapeutic agents. This peculiarity has raised a lot of interest over the last two decades in drug delivery, and in situations where biological barriers pose a serious obstacle to the efficient delivery of active substances. [12,13] As an example, efficient drug delivery through the skin is a challenge for cosmetologists and dermatologists. For our own good, the skin is a strong barrier for outside penetration, especially thanks to the outmost layers of the epidermis being composed mainly of dead corneocytes surrounded by lipid layers. Studies have shown that even when using plasma treatment to render the skin more permeable, carriers larger than 700 nm are unable to penetrate it. [14] A second example is the intravenous administration of drug-filled carriers that requires sizes in the

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Section: Artificial Polypeptide-based Simple Coacervatesmentioning

confidence: 99%

Protein‐Based Encapsulation Strategies: Toward Micro‐ and Nanoscale Carriers with Increased Functionality

et al. 2022

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“…A large number of studies have shown that LLPS are formed in membraneless aggregates including nuclear spots and stress particles to maintain genome stability, transcriptional regulation, immune-related signal pathways, cellular stress response, cell proliferation, autophagy-related signal pathways, etc. ( Abbas et al, 2021 ; Guo et al, 2021 ; Peng et al, 2021 ; Su et al, 2021 ). Early research shows that abnormal LLPS plays a crucial role in the progression of neurodegenerative diseases ( Zbinden et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Systematic Analysis of Molecular Characterization and Clinical Relevance of Liquid–Liquid Phase Separation Regulators in Digestive System Neoplasms

Zhang

Feng

et al. 2022

Front. Cell Dev. Biol.

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Background: The role of liquid–liquid phase separation (LLPS) in cancer has also attracted more and more attention, which is found to affect transcriptional regulation, maintaining genomic stability and signal transduction, and contribute to the occurrence and progression of tumors. However, the role of LLPS in digestive system tumors is still largely unknown.Results: Here, we characterized the expression profiles of LLPS regulators in 3 digestive tract tumor types such as COAD, STAD, and ESCA with The Cancer Genome Atlas (TCGA) data. Our results for the first time showed that LLPS regulatory factors, such as Brd4, FBN1, and TP53, were frequently mutated in all types of digestive system tumors. Variant allele frequency (VAF) and APOBEC analysis demonstrated that genetic alterations of LLPS regulators were related to the progression of digestive system neoplasms (DSNs), such as TP53, NPHS1, TNRC6B, ITSN1, TNPO1, PML, AR, BRD4, DLG4, and PTPN1. KM plotter analysis showed that the mutation status of LLPS regulators was significantly related to the overall survival (OS) time of DSNs, indicating that they may contribute to the progression of DSN. The expression analysis of LLPS regulatory factors showed that a variety of LLPS regulatory factors were significantly dysregulated in digestive system tumors, such as SYN2 and MAPT. It is worth noting that we first found that LLPS regulatory factors were significantly correlated with tumor immune infiltration of B cells, CD4+ T cells, and CD8+ T cells in digestive system tumors. Bioinformatics analysis showed that the LLPS regulators’ expression was closely related to multiple signaling, including the ErbB signaling pathway and T-cell receptor signaling pathway. Finally, several LLPS signatures were constructed and had a strong prognostic stratification ability in different digestive gland tumors. Finally, the results demonstrated the LLPS regulators’ signature score was significantly positively related to the infiltration levels of CD4+ T cells, neutrophil cells, macrophage cells, and CD8+ T cells.Conclusion: Our study for the first time showed the potential roles of LLPS regulators in carcinogenesis and provide novel insights to identify novel biomarkers for the prediction of immune therapy and prognosis of DSNs.

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“…Recent work has demonstrated that some micro-compartments and protocell systems could compartmentalize (bio)chemical reactions, and act as catalytic microreactors or reaction localization centers with potential for prebiotic peptide ligation. [11][12][13][14][15][16] In particular, membraneless compartments based on complex coacervates have been considered as versatile protocell models in the origins of life research. 5,[16][17][18][19] Coacervate droplets are formed spontaneously by liquid-liquid phase separation, resulting in a polymer-or peptide-rich, cell-sized dense coacervate phase, and a coexisting dilute phase.…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14][15][16] In particular, membraneless compartments based on complex coacervates have been considered as versatile protocell models in the origins of life research. 5,[16][17][18][19] Coacervate droplets are formed spontaneously by liquid-liquid phase separation, resulting in a polymer-or peptide-rich, cell-sized dense coacervate phase, and a coexisting dilute phase. These membraneless droplets can easily take up and concentrate guest molecules from their surroundings due to charge complementarity or hydrophobicity.…”

Section: Introductionmentioning

confidence: 99%

“…These membraneless droplets can easily take up and concentrate guest molecules from their surroundings due to charge complementarity or hydrophobicity. 16,20,21 The ability to up-concentrate and exchange guests make the coacervate droplets capable of supporting biochemical reactions, and sometimes enhancing the activity of catalysts, such as ribozymes, 12,13 or enzymes in cascade reactions, 15,22 thereby increasing the overall rate. Recent work has demonstrated that coacervate droplets can be active, 18,23 and that their formation and dissolution can be regulated by environmental changes, such as pH, 24,25 temperature, 26,27 light, 28 enzymatic reactions, 23,[29][30][31] or fuel-driven chemical reaction cycles.…”

Section: Introductionmentioning

confidence: 99%

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Selective amide bond formation in redox-active coacervate protocells

Wang

Abbas

Wang

et al. 2021

Preprint

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Membraneless compartments, like complex coacervates droplets, are promising protocell models because of their ability to sequester a wide range of guest molecules and their catalytic properties. However, it remains unclear how the building blocks of life, including peptides, could be synthesized from primitive precursor molecules inside such protocells. Here, we develop a new protocell model formed by phase separation of prebiotically relevant small redox-active ferricyanide (Fe(CN)_6^{3−})/ferrocyanide (Fe(CN)_6^{4−}) molecules and a cationic peptide. The assembly of these coacervate protocells can be regulated by redox chemistry and they act as oxidizing hubs for sequestered metabolites, such as NAD(P)H, and fiber precursors. Interestingly, we show that the oxidizing potential of ferricyanide inside coacervates can be harnessed to drive the selective formation of amide bonds between prebiotically relevant amino thioacids and amino acids or peptides. We demonstrate that aminoacylation is enhanced in Fe(CN)_6^{3−}/peptide coacervate dispersions compared to the surrounding dilute phase, and selective for amino acids that interact less strongly with the coacervates. We finally use this amide bond formation to create self-reinforcing coacervates by reacting hydrophobic amino thioacids to amines on the protocell scaffold and show that this significantly enhances their salt resistance. These results provide an important step towards the prebiotically relevant integration of redox chemistry in cell-like compartments.

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A short peptide synthon for liquid–liquid phase separation

Cited by 166 publications

References 64 publications

Protein‐Based Encapsulation Strategies: Toward Micro‐ and Nanoscale Carriers with Increased Functionality

Protein‐Based Encapsulation Strategies: Toward Micro‐ and Nanoscale Carriers with Increased Functionality

Systematic Analysis of Molecular Characterization and Clinical Relevance of Liquid–Liquid Phase Separation Regulators in Digestive System Neoplasms

Selective amide bond formation in redox-active coacervate protocells

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