Ligand–Receptor Interaction Catalyzes the Aggregation of Small Molecules To Induce Cell Necroptosis

Shi, Junfeng; Du, Xuewen; Huang, Yibing; Zhou, Jie; Yuan, Dan; Wu, Dongdong; Zhang, Shijin; Haburcak, Richard; Epstein, Irving R.; Xu, Bing

doi:10.1021/ja5100417

Cited by 46 publications

(44 citation statements)

References 51 publications

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“…Supramolecular catalysis, which utilizes enzymes 10 or synthetic catalysts (i.e., acids or bases) 23 to control the kinetics of assembly/disassembly, affords spatiotemporal regulation over the system. In addition, the ligand-receptor 24 or protein-protein interactions 25 could provide another level of precision to design controllable dynamic assemblies. In the following sections, we discuss recent studies on controlling the dynamic assembly, disassembly, or both for a variety of applications in biomedicine.…”

Section: Rational Designmentioning

confidence: 99%

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Supramolecular catalysis and dynamic assemblies for medicine

et al. 2017

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In this review, supramolecular catalysis refers to the integration of catalytic process with molecular self-assembly driven by noncovalent interactions, and dynamic assemblies are the assemblies that form and dissipate reversibly. Cells extensively employ supramolecular catalysis and dynamic assemblies for controlling their complex functions. The dynamic generation of supramolecular assemblies of small molecules has made a considerable progress in the last decade, though the disassembly processes remain underexplored. Here, we discuss the regulation of dynamic assemblies via self-assembly and disassembly processes for therapeutics and diagnostics. We first briefly introduce the self-assembly and disassembly processes in the context of cells, which provide the rationale for designing approaches to control the assemblies. Then, we describe recent advances in designing and regulating the self-assembly and disassembly of small molecules, especially for molecular imaging and anticancer therapeutics. Finally, we provide a perspective on future directions of the research on supramolecular catalysis and dynamic assemblies for medicine.

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Section: Rational Designmentioning

confidence: 99%

“…In addition to enzymatic reaction, ligand-receptor interactions also provide precise control over the production of assemblies. 24 The interaction of vancomycin with a D-Ala-D-Ala-containing peptide derivative 5 (Fig. 2F) catalyzes the aggregation of 5 (Fig.…”

Section: Assemblymentioning

confidence: 99%

Supramolecular catalysis and dynamic assemblies for medicine

et al. 2017

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“…[64] As shown in Fig. 12a, via ligand-receptor interactions, two molecules of vancomycin (Van) bind with four molecules of Fmoc-Lys-Gly-Gly-D-Ala-D-Ala ( 14 ).…”

Section: Ligand-receptor Interaction Catalyzes the Formation Of Namentioning

confidence: 99%

Nanoscale assemblies of small molecules control the fate of cells

Shi

2015

Nano Today

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Being driven by non-covalent interactions, the formation of functional assemblies (or aggregates) of small molecules at nanoscale is a more common process in water than one would think. While most efforts on self-assembly in cellular environment concentrate on the assemblies of proteins (e.g., microtubules or amyloid fibers), nanoscale assemblies of small molecules are emerging functional entities that exhibit important biological function in cellular environments. This review describes the increasing efforts on the exploration of nanoscale assemblies of small molecules that largely originate from the serendipitous observations in research fields other than nanoscience and technology. Specifically, we describe that nanoscale assemblies of small molecules exhibit unique biological functions in extracellular and intracellular environment, thus inducing various cellular responses, like causing cell death or promoting cell proliferation. We first survey certain common feature of nanoscale molecular assemblies, then discuss several specific examples, such as, nanoscale assemblies of small peptides accumulated in the cells for selectively inhibiting cancer cells via promiscuous interactions with proteins, and nanoscale assemblies of a glycoconjugate for promoting the proliferation of stem cells or for suppressing immune responses. Subsequently, we emphasize the spatiotemporal control of nanoscale assemblies for controlling the cell fate, particularly illustrate a paradigm-shifting approach—enzyme-instructed self-assembly (EISA), that is, the integration of enzymatic reaction and self-assembly—for generating nanoscale assemblies from innocuous monomers for selectively inhibiting cancer cells. Moreover, we introduce a convenient assay for proteomic study of the proteins that interact with nanoscale assemblies of small molecules in cellular environment. Furthermore, we introduce the use of ligand-receptor interaction to catalyze the formation of nanoscale assemblies. By illustrating these experimental strategies for controlling the formation of nanoscale assemblies of small molecules and for identifying their corresponding protein targets, we aim to highlight that, though not being defined at the genetic level, nanoscale assemblies of small molecules are able to perform many critical biological functions. We envision that nanoscale assemblies of small molecules are a new frontier at the intersection of nanoscience and cell biology and biomedicine. In addition, we discuss the challenges and perspectives of relevant potential biomedical applications of nanoscale assemblies of small molecules.

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“…9 The resulting aggregates 1b &Van likely adhere to cell surface to cause cell death, which is consistent with our recent discovery that the aggregates catalysed by ligand-receptor interaction are able to inhibit the proliferation of cells. 6 The lower IC 50 of 1a &Van than that of 1b &Van may result from the self-assembly of certain amounts of 1b on cell surface due to the dephosphorylation of 1a . 8, 9, 11 In another experiment, after the incubation of HeLa cells with 1a for 12h, the addition of Van at equal molar ratio inhibits HeLa cells proliferation, but IC 50 value is slightly higher (385 µM (Fig.S5)) and is comparable to that of the mixture of 1b &Van.…”

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confidence: 99%

“…These results, thus, indicate that enzyme catalysis and ligand-receptor interaction generate the aggregates for inhibiting the proliferation of the HeLa cells. 6 …”

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Enzyme transformation to modulate the ligand–receptor interactions between small molecules

Shi

Yuan

et al. 2015

Chem. Commun.

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Enzymatic transformation is a fundamental process to control ligand-receptor interactions among proteins for signal transduction in cells. Here we report the first example of enzymatic transformation regulated ligand-receptor interactions of small molecules, in which enzymatic reaction changes the stoichiometry of the ligand-receptor binding from 1:1 to 1:2. We also show that this unique integration of enzymatic transformation and ligand-receptor interactions of small molecules is able to affect the fate of cells.

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Ligand–Receptor Interaction Catalyzes the Aggregation of Small Molecules To Induce Cell Necroptosis

Cited by 46 publications

References 51 publications

Supramolecular catalysis and dynamic assemblies for medicine

Supramolecular catalysis and dynamic assemblies for medicine

Nanoscale assemblies of small molecules control the fate of cells

Enzyme transformation to modulate the ligand–receptor interactions between small molecules

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