Cyclic Peptidomimetics as Inhibitor for miR-155 Biogenesis

Hao, Yan; Zhou, Mi; Bhattarai, Umesh; Song, Yabin; Zheng, Mengmeng; Cai, Jianfeng; Liang, Fu‐Sen

doi:10.1021/acs.molpharmaceut.8b01247

Cited by 23 publications

(19 citation statements)

References 44 publications

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“…The result showed that eight beads had unambiguous MS/MS fragmentation patterns, suggesting the quality of the beads was excellent. Subsequently, the high-throughput screening for the HER2 protein was directly performed with the library using the protocol detailed in the Supporting information 22 , 23 , 24 . Briefly, to avoid the nonspecific binding and to improve the screening efficiency, prescreening was firstly performed, then the OBTC library was incubated with Fc-Tagged recombinant HER2 protein, followed by incubation with Goat anti-human IgG Fc cross adsorbed secondary antibody labeled with dylight 549 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1 ), which could fold into well-defined protein-like helical structures stabilized by intramolecular hydrogen bond 17 , 18 , 19 , 20 , providing a novel strategy to rationally design helical mimetics of important protein domain for protein surface recognition as well as disrupt critical protein–protein interactions 21 . Meanwhile, the unique γ -AApeptides backbone also provides a novel platform with remarkable stability and diversity that has been used to develop combinatorial libraries, from which unnatural ligands could be identified to bind to proteins or nucleic acids with high specificity and affinity 22 , 23 , 24 . In the current study, we report a strategy to develop new generation of artificial antibody based on γ -AApeptides.…”

Section: Introductionmentioning

confidence: 99%

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Peptidomimetic-based antibody surrogate for HER2

Zheng

Zhou

et al. 2021

Acta Pharmaceutica Sinica B

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Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on γ -AApeptides to target HER2 extracellular domain (ECD). To achieve this, we synthesized a one-bead-two-compound (OBTC) library containing 320,000 cyclic γ -AApeptides, from which we identified a γ -AApeptide, M-3-6, that tightly binds to HER2 selectively. Subsequently, we designed an antibody-like dimer of M-3-6, named M-3-6-D, which showed excellent binding affinity toward HER2 comparable to monoclonal antibodies. Intriguingly, M-3-6-D was completely resistant toward enzymatic degradation. In addition, it could effectively inhibit the phosphorylation of HER2, as well as the downstream signaling pathways of AKT and ERK. Furthermore, M-3-6-D also efficiently inhibited cell proliferation in vitro , and suppressed tumor growth in SKBR3 xenograft model in vivo , implying its therapeutic potential for the treatment of cancers. Its small molecular weight, antibody-like property, resistance to proteolysis, may enable it a new generation of artificial antibody surrogate. Furthermore, our strategy of artificial antibody surrogate based on dimers of cyclic γ -AApeptides could be applied to a myriad of disease-related receptor targets in future.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peptidomimetic-based antibody surrogate for HER2

Zheng

Zhou

et al. 2021

Acta Pharmaceutica Sinica B

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“…Anti-miR155 oligonucleotides and antagomir have been designed for various cancer treatments (42,43). Small molecule-based cyclic peptidomimetics had shown an inhibitory effect on miR155 biogenesis (44). MLN4924 is an inhibitor of the NEDD8-activating enzyme.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-155 regulates osteogenesis and bone mass phenotype via targeting S1PR1 gene

Zheng

et al. 2022

Preprint

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MicroRNA-155 (miR155) is overexpressed in various inflammatory diseases and cancer, in which bone resorption and osteolysis are frequently observed. However, the role of miR155 on osteogenesis and bone mass phenotype is still unknown. Here, we report a low bone mass phenotype in the long bone of miR155-Tg mice compared with control mice. In contrast, miR155-KO mice showed a high bone mass phenotype. miR155-KO mice showed robust bone regeneration in the ectopic and orthotopic model, but miR155-Tg mice showed compromised bone regeneration compared with the control mice. Similarly, the osteogenic differentiation potential of bone marrow stromal stem cells (BMSCs) from miR155-KO mice was robust and miR155-Tg was compromised compared with that of control mice. Moreover, miR155 knockdown in BMSCs from control mice showed higher osteogenic differentiation potential, supporting the results from miR155-KO mice. TargetScan analysis predicted S1PR1 as a target gene of miR155, which was further confirmed by luciferase assay and miR155 knockdown. S1PR1 overexpression in BMSCs robustly promoted osteogenic differentiation without affecting cell viability and proliferation. Thus, miR155 showed a catabolic effect on osteogenesis and bone mass phenotype via interaction with the S1PR1 gene, suggesting inhibition of miR155 as a potential strategy for bone regeneration and bone defect healing.

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“…The stable stem-loop structures of miRNA make them attractive targets for library screening techniques as they can easily be maintained in the correct fold during selection. An affinity-based screening protocol to identify macrocyclic peptide inhibitors to target pre-miR-155 was reported by Yan et al (2019) Downregulation of miR-155 was previously found to reduce breast cancer cell growth and therefore considered to be an attractive target ( Mattiske et al, 2012 ). A library (3.2 × 10 5 ) of macrocyclic peptides was prepared via split-and-pool synthesis using the one bead two components (OBTC) method containing various γ-substituted- N -acylated- N -aminoethylamino acids (γ-AA) as building blocks ( Shi et al, 2017 ).…”

Section: Rna-binding Cyclic Peptides Identified Via ...mentioning

confidence: 99%

RNA-Binding Macrocyclic Peptides

Pal

Hart

2022

Front. Mol. Biosci.

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Being able to effectively target RNA with potent ligands will open up a large number of potential therapeutic options. The knowledge on how to achieve this is ever expanding but an important question that remains open is what chemical matter is suitable to achieve this goal. The high flexibility of an RNA as well as its more limited chemical diversity and featureless binding sites can be difficult to target selectively but can be addressed by well-designed cyclic peptides. In this review we will provide an overview of reported cyclic peptide ligands for therapeutically relevant RNA targets and discuss the methods used to discover them. We will also provide critical insights into the properties required for potent and selective interaction and suggestions on how to assess these parameters. The use of cyclic peptides to target RNA is still in its infancy but the lessons learned from past examples can be adopted for the development of novel potent and selective ligands.

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Cyclic Peptidomimetics as Inhibitor for miR-155 Biogenesis

Cited by 23 publications

References 44 publications

Peptidomimetic-based antibody surrogate for HER2

Peptidomimetic-based antibody surrogate for HER2

MicroRNA-155 regulates osteogenesis and bone mass phenotype via targeting S1PR1 gene

RNA-Binding Macrocyclic Peptides

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