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Enzyme-Instructed Peptide Assemblies Selectively Inhibit Bone Tumors.

ABSTRACT: Alkaline phosphatases (ALP) contribute to immunosuppression in solid tumors, but they, unfortunately, are "undruggable". Here we report enzyme-instructed assembly of peptides for selectively inhibiting the tumors that overexpress ALP. We developed a precursor with two parts; an amphiphilic, self-assembling peptides joined to a hydrophilic block (i.e., tyrosine phosphate). ALP, overexpressed on and in osteosarcoma cancer cells (e.g., Saos-2), cleaves the phosphates from the tyrosine residue of the precursor and triggers the self-assembly of the resulting peptides. Being selectively formed on and inside the cancer cells, the peptide assemblies induce the cancer cell death and efficiently inhibit the tumor growth in an orthotopic osteosarcoma mice model without harming normal organs. Accordingly, the peptide assemblies significantly improve the survival ratio of metastatic tumor bearing mice. Without relying on inhibiting ALP, this approach integrates enzyme reaction and molecular self-assembly for generating peptide fibrils as potential anticancer therapeutics.

SUBMITTER: Feng Z

PROVIDER: S-EPMC6758912 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Enzyme-Instructed Peptide Assemblies Selectively Inhibit Bone Tumors.

Feng Zhaoqianqi Z Han Xiuguo X Wang Huaimin H Tang Tingting T Xu Bing B

Chem 20190722 9

Alkaline phosphatases (ALP) contribute to immunosuppression in solid tumors, but they, unfortunately, are "undruggable". Here we report enzyme-instructed assembly of peptides for selectively inhibiting the tumors that overexpress ALP. We developed a precursor with two parts; an amphiphilic, self-assembling peptides joined to a hydrophilic block (i.e., tyrosine phosphate). ALP, overexpressed on and in osteosarcoma cancer cells (e.g., Saos-2), cleaves the phosphates from the tyrosine residue of th ...[more]

PMID: 31552305

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Project description:Recent studies have demonstrated that enzyme-instructed self-assembly (EISA) in extra- or intracellular environments can serve as a multistep process for controlling cell fate. There is little knowledge, however, about the kinetics of EISA in the complex environments in or around cells. Here, we design and synthesize three dipeptidic precursors (ld-1-SO3, dl-1-SO3, dd-1-SO3), consisting of diphenylalanine (l-Phe-d-Phe, d-Phe-l-Phe, d-Phe-d-Phe, respectively) as the backbone, which are capped by 2-(naphthalen-2-yl)acetic acid at the N-terminal and by 2-(4-(2-aminoethoxy)-4-oxobutanamido)ethane-1-sulfonic acid at the C-terminal. On hydrolysis by carboxylesterases (CES), these precursors result in hydrogelators, which self-assemble in water at different rates. Whereas all three precursors selectively kill cancer cells, especially high-grade serous ovarian carcinoma cells, by undergoing intracellular EISA, dl-1-SO3 and dd-1-SO3 exhibit the lowest and the highest activities, respectively, against the cancer cells. This trend inversely correlates with the rates of converting the precursors to the hydrogelators in phosphate-buffered saline. Because CES exists both extra- and intracellularly, we use kinetic modeling to analyze the kinetics of EISA inside cells and to calculate the cytotoxicity of each precursor for killing cancer cells. Our results indicate that (i) the stereochemistry of the precursors affects the morphology of the nanostructures formed by the hydrogelators, as well as the rate of enzymatic conversion; (ii) decreased extracellular hydrolysis of precursors favors intracellular EISA inside the cells; (iii) the inherent features ( e.g., self-assembling ability and morphology) of the EISA molecules largely dictate the cytotoxicity of intracellular EISA. As the kinetic analysis of intracellular EISA, this work elucidates how the stereochemistry modulates EISA in the complex extra- and/or intracellular environment for developing anticancer molecular processes. Moreover, it provides insights for understanding the kinetics and cytotoxicity of aggregates of aberrant proteins or peptides formed inside and outside cells.

Dataset Information

Enzyme-Instructed Peptide Assemblies Selectively Inhibit Bone Tumors.

Publications

Enzyme-Instructed Peptide Assemblies Selectively Inhibit Bone Tumors.

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