One-Bead–Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2

Shi, Yan; Challa, Sridevi; Sang, Peng; She, Fengyu; Li, Chunpu; Gray, Geoffrey; Nimmagadda, Alekhya; Teng, P. K.; Odom, Timothy; Wang, Yan; Vaart, Arjan van der; Li, Qi; Cai, Jianfeng

doi:10.1021/acs.jmedchem.7b01280

Cited by 33 publications

(50 citation statements)

References 56 publications

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“…We next measured the binding affinity of sulfono-γ-AApeptide 2 toward β-catenin using a fluorescence polarization assay. In our assay, the binding affinity of BCL9 peptide 1 exhibited a K d value of 0.97 μM (Table 1), consistent with previous reports (19,29). Excitingly, the first sulfono-γ-AApeptide sequence 2 that we designed, with a shorter length than the BCL9 peptide 1, had a K d value of 0.43 μM, which is already twofold more affinitive to β-catenin than BCL9 peptide 1.…”

Section: Resultssupporting

confidence: 90%

“…As a new class of proteolytically stable peptidomimetics, γ-AApeptides have emerged as effective peptidomimetics that play important roles in chemical biology and biomedical sciences (17)(18)(19). Specifically, sulfono-γ-AApeptides have been shown to have excellent folding stability to adopt a series of helical structures with a well-defined hydrogen-bonding pattern (20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

“…In sulfono-γ-AApeptides, one-half of the side chains are introduced by sulfonyl chlorides, providing enormous chemical diversity ( Fig. 1A) (17)(18)(19). In particular, we recently reported the X-ray crystal structures of a series of homogeneous L-sulfono-γ-AA foldamers (24), which form well-defined left-handed 4 14 helices ( Fig.…”

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confidence: 99%

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Inhibition of β-catenin/B cell lymphoma 9 protein−protein interaction using α-helix–mimicking sulfono-γ-AApeptide inhibitors

Sang

Zhang

Shi

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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104

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The rational design of α-helix-mimicking peptidomimetics provides a streamlined approach to discover potent inhibitors for protein−protein interactions (PPIs). However, designing cell-penetrating long peptidomimetic scaffolds equipped with various functional groups necessary for interacting with large protein-binding interfaces remains challenging. This is particularly true for targeting β-catenin/ BCL9 PPIs. Here we designed a series of unprecedented helical sulfono-γ-AApeptides that mimic the binding mode of the α-helical HD2 domain of B Cell Lymphoma 9 (BCL9). Our studies show that sulfono-γ-AApeptides can structurally and functionally mimic the α-helical domain of BCL9 and selectively disrupt β-catenin/BCL9 PPIs with even higher potency. More intriguingly, these sulfonoγ-AApeptides can enter cancer cells, bind with β-catenin and disrupt β-catenin/BCL9 PPIs, and exhibit excellent cellular activity, which is much more potent than the BCL9 peptide. Furthermore, our enzymatic stability studies demonstrate the remarkable stability of the helical sulfono-γ-AApeptides, with no degradation in the presence of pronase for 24 h, augmenting their biological potential. This work represents not only an example of helical sulfono-γ-AApeptides that mimic α-helix and disrupt protein-protein interactions, but also an excellent example of potent, selective, and cell-permeable unnatural foldameric peptidomimetics that disrupt the β-catenin/BCL9 PPI. The design of helical sulfono-γ-AApeptides may lead to a new strategy to modulate a myriad of protein-protein interactions.α-helix mimetics | β-catenin | B-cell lymphoma 9 | protein-protein interactions | inhibitors Author contributions: H.J. and J.C. designed research; P.S., M.Z., Y.S., and C.L. performed research; P.S., S.A., Q.L., H.J., and J.C. analyzed data; and P.S., H.J., and J.C. wrote the paper.The authors declare no conflict of interest. This article is a PNAS Direct Submission.Published under the PNAS license. 1 P.S., M.Z., and Y.S. contributed equally to this work.

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Section: Resultssupporting

confidence: 90%

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confidence: 99%

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Inhibition of β-catenin/B cell lymphoma 9 protein−protein interaction using α-helix–mimicking sulfono-γ-AApeptide inhibitors

Sang

Zhang

Shi

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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104

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“…[1][2][3][4][5][6][7] They are also important in molecular recognition and materials sciences. Natural and synthetic macrocycles often exhibit useful biological activities that allow them to function as drugs or lead compounds for drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Syntheses of Bis‐Triazole Linked Carbohydrate Based Macrocycles and Their Applications for Accelerating Copper Sulfate Mediated Click Reaction

et al. 2019

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Macrocyclic compounds play an important role in many research fields including drug discovery and development, bioorganic chemistry, and materials sciences. Carbohydrate‐based macrocycles are important compounds with unique structures and many potential applications. In this study, we have designed and synthesized a series of 1,2,3‐triazole linked and pyranose embedded macrocycles in short steps through the copper (I) catalyzed azide and alkyne cycloaddition reactions (CuAACs). Eight non‐symmetrical glucosamine based and bis‐triazole linked macrocycles have been synthesized starting from the readily available N‐acetyl‐d‐glucosamine. These triazole‐linked glycomacrocycles showed remarkable reaction rate accelerations for CuSO4 mediated azide and alkyne cycloaddition reactions in aqueous mixtures. Several azides including a sugar azide, which react sluggishly with alkynes, have been accelerated with the synthesized macrocycles. The benzoylated macrocycles with three methylene linkage at anomeric positions were the most effective among the eight macrocycles.

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“…Each monomeric unit of γ-AApeptides is equivalent to a dipeptide motif in a conventional α-peptide; thus a γ-AApeptide can project an identical number of functional groups as an α-peptide of the equal length. γ-AApeptides have been shown to form well-defined helical structures [39][40][41] , target bacterial membranes [42][43][44] , and specifically bind to protein surfaces to modulate protein functions and cellular activities [45][46][47][48] .…”

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confidence: 99%

γ-AApeptides–based Small Molecule Ligands That Disaggregate Human Islet Amyloid Polypeptide

Bolarinwa

Khadka

et al. 2020

Sci Rep

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the abnormal folding and aggregation of functional proteins into amyloid is a typical feature of many age-related diseases, including type ii diabetes. Growing evidence has revealed that the prevention of aggregate formation in culprit proteins could retard the progression of amyloid diseases. Human Amylin, also known as human islet amyloid polypeptide (hiApp), is the major factor for categorizing Type II diabetes as an amyloid disease. Specifically, hIAPP has a great aggregation potential, which always results in a lethal situation for the pancreas. Many peptide inhibitors have been constructed from the various segments of the full-length hiApp peptide; however, only a few have their origin from the screening of combinatorial peptidomimetic library. In this study, based on HW-155, which was previously discovered from a one-bead-one compound (oBoc) library to inhibit Aβ 40 aggregation, we investigated eight (8) analogues and evaluated their amyloid-prevention capabilities for inhibiting fibrillization of hIAPP. Characterization studies revealed that all analogues of HW-155, as well as HW-155, were effective inhibitors of the fibril formation by hIAPP .

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One-Bead–Two-Compound Thioether Bridged Macrocyclic γ-AApeptide Screening Library against EphA2

Cited by 33 publications

References 56 publications

Inhibition of β-catenin/B cell lymphoma 9 protein−protein interaction using α-helix–mimicking sulfono-γ-AApeptide inhibitors

Inhibition of β-catenin/B cell lymphoma 9 protein−protein interaction using α-helix–mimicking sulfono-γ-AApeptide inhibitors

Syntheses of Bis‐Triazole Linked Carbohydrate Based Macrocycles and Their Applications for Accelerating Copper Sulfate Mediated Click Reaction

γ-AApeptides–based Small Molecule Ligands That Disaggregate Human Islet Amyloid Polypeptide

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