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Inhibition of Β-Catenin/B Cell Lymphoma 9 Protein−Protein Interaction Using Α-Helix–Mimicking Sulfono-Γ-Aapeptide Inhibitors

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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 Peng Sanga,1, Min Zhangb,1, Yan Shia,1, Chunpu Lia,c,d, Sami Abdulkadira,QiLic,d,2, Haitao Jib,2, and Jianfeng Caia,2 aDepartment of Chemistry, University of South Florida, Tampa, FL 33620; bDrug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; cDepartment of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; and dAcademy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China Edited by Samuel H. Gellman, University of Wisconsin–Madison, Madison, WI, and approved April 22, 2019 (received for review November 16, 2018) The rational design of α-helix–mimicking peptidomimetics pro- compared with that of α-helix (5.4 Å), as well as the remarkable vides a streamlined approach to discover potent inhibitors for pro- stability of sulfono-γ-AApeptides, we envisioned that helical sul- tein−protein interactions (PPIs). However, designing cell-penetrating fono-γ-AApeptides could be adapted to develop a new class of helical long peptidomimetic scaffolds equipped with various functional mimetics that disrupt α-helix-mediated protein–protein interactions. groups necessary for interacting with large protein-binding interfaces With the aim of developing new PPIs for various biological remains challenging. This is particularly true for targeting β-catenin/ targets, we wondered whether B Cell Lymphoma 9 (BCL9) (25– BCL9 PPIs. Here we designed a series of unprecedented helical sul- 39), previously shown to engage its α-helical HD2 domain to fono-γ-AApeptides that mimic the binding mode of the α-helical HD2 interact with β-catenin (Fig. 2), could be used to develop pep- domain of B Cell Lymphoma 9 (BCL9). Our studies show that sul- tidomimetic helical foldamers based on sulfono-γ-AApeptides. fono-γ-AApeptides can structurally and functionally mimic the The Wnt/β-catenin signaling pathway plays important roles in α-helical domain of BCL9 and selectively disrupt β-catenin/BCL9 PPIs embryonic development and tissue homeostasis, as well as in with even higher potency. More intriguingly, these sulfono- several types of human cancer, such as colorectal cancer, breast γ-AApeptides can enter cancer cells, bind with β-catenin and disrupt – cancer, melanoma, prostate cancer, and others (40 43). BIOCHEMISTRY β-catenin/BCL9 PPIs, and exhibit excellent cellular activity, which is As a central mediator of the signaling, β-catenin controls the ex- much more potent than the BCL9 peptide. Furthermore, our enzy- pression of several key genes that regulate the cell cycle and apo- matic stability studies demonstrate the remarkable stability of the ptosis. As the matter of fact, transcriptional activation of Wnt/ γ helical sulfono- -AApeptides, with no degradation in the presence β-catenin signaling pathway is dependent on formation of the of pronase for 24 h, augmenting their biological potential. This work β-catenin supercomplex involving BCL9 or BCL9-like (B9L), as well γ represents not only an example of helical sulfono- -AApeptides that as the T cell factor (Tcf)/lymphoidenhancer-bindingfactor(Lef) α – mimic -helix and disrupt protein protein interactions, but also an family of transcriptional factors (37). Specifically, BCL9 functions as a excellent example of potent, selective, and cell-permeable unnatural scaffolding structure of the Wnt enhanceosome and brings β-catenin β foldameric peptidomimetics that disrupt the -catenin/BCL9 PPI. The to TCF/LEF to transcribe specific Wnt target genes, leading to cell design of helical sulfono-γ-AApeptides may lead to a new strategy to – growth, proliferation, and differentiation (44). As such, molecules modulate a myriad of protein protein interactions. that disrupt BCL9/β-catenin protein–protein interaction could inhibit α-helix mimetics | β-catenin | B-cell lymphoma 9 | protein–protein interactions | inhibitors Significance The design of cell-penetrating long peptidomimetic scaffolds he development of peptidomimetic helical foldamers for for interacting with large protein binding interfaces is chal- applications in chemical biology and drug discovery has attrac- T lenging because they involve various necessary functional tedmuchinterestinthefieldofmedicinalchemistry.Helicalfol- groups. Here we report the first series of helical sulfono- damers are commonly featured with many attractive merits, such as γ-AApeptides that disrupt protein–protein interactions. Spe- enhanced resistance to proteolytic degradation and high sequence cifically, we discovered that these helical mimetics can struc- diversity (1–8), and have been explored extensively for inhibition of turally and functionally mimic the B Cell Lymphoma 9 (BCL9) protein–protein interactions (PPIs) (9–13). Nevertheless, the tar- helix and disrupt cancer-related β-catenin/BCL9 protein–pro- geting of intracellular proteins still entails significant challenges (14– tein interaction in cells with excellent potency and specificity. 16), largely due to the limited availability of molecular frameworks Enzymatic stability studies demonstrate the remarkable sta- of peptidomimetic peptides. bility of the helical sulfono-γ-AApeptides, augmenting their As a new class of proteolytically stable peptidomimetics, γ biological potential. This strategy could be adapted to target a -AApeptides have emerged as effective peptidomimetics that myriad of other disease-related protein–protein interactions. play important roles in chemical biology and biomedical sciences – γ (17 19). Specifically, sulfono- -AApeptides have been shown to Author contributions: H.J. and J.C. designed research; P.S., M.Z., Y.S., and C.L. performed have excellent folding stability to adopt a series of helical research;P.S.,S.A.,Q.L.,H.J.,andJ.C.analyzeddata;andP.S.,H.J.,andJ.C.wrote structures with a well-defined hydrogen-bonding pattern (20–24). the paper. In sulfono-γ-AApeptides, one-half of the side chains are in- The authors declare no conflict of interest. troduced by sulfonyl chlorides, providing enormous chemical This article is a PNAS Direct Submission. diversity (Fig. 1A) (17–19). In particular, we recently reported Published under the PNAS license. the X-ray crystal structures of a series of homogeneous L-sul- 1P.S., M.Z., and Y.S. contributed equally to this work. γ fono- -AA foldamers (24), which form well-defined left-handed 2To whom correspondence may be addressed. Email: [email protected], Haitao.Ji@ 414 helices (Fig. 1 B and C). Intriguingly, the side chains of sul- moffitt.org, or [email protected]. fono-γ-AApeptides are aligned perfectly on the top of one another This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. with a pitch of 5.1 Å. Based on the precise 3D arrangement of 1073/pnas.1819663116/-/DCSupplemental. their side functional groups, their close similarity in helical pitch www.pnas.org/cgi/doi/10.1073/pnas.1819663116 PNAS Latest Articles | 1of6 Downloaded by guest on September 24, 2021 A C multiple myeloma. It is envisioned that unnatural peptidomi- metic inhibitors of β-catenin/BCL9 PPI would be appealing be- cause they can mimic peptide helices while being highly resistant to proteolytic degradation. However, to the best of our knowl- edge, to date there has been no report on the development of potent unnatural peptidomimetic inhibitors to disrupt β-catenin/ BCL9 PPI. This is possibly due to the fact that known peptidic foldamers do not efficiently mimic the long α-helix, as well as to the limited availability of scaffolds and molecular frameworks. With the availability of helical sulfono-γ-AApeptide scaffold, B we questioned whether sulfono-γ-AApeptides can be designed to effectively disrupt the β-catenin/BCL9 PPI. If so, this would offer a new template for generating potent helical peptidomimetics that inhibit a variety of medicinally relevant PPIs. In view of the folding pattern (Fig. 2 C–F), we believe that our sulfono-γ-AApeptides can effectively mimic BCL9, because the side chains of sulfono- γ-AApeptides could be designed to mimic the critical residues of 5.1 Å the α-helix of BCL9 HD2 domain. Here we report the develop- ment of some unnatural peptidomimetics that are highly effective γ Fig. 1. (A) The chemical structure of sulfono- -AApeptides; a and b denote the for inhibiting β-catenin/BCL9 PPI. chiral side chain and the sulfonamido side chain from the building block, re- γ spectively. (B) The crystal structure of a sulfono- -AApeptide. (C)TopviewofB. Results and Discussion Design and Biological Activity of Sulfono-γ-AApeptides. Our design Wnt/β-catenin signaling transduction and thus could be developed as was straightforward. As shown in Fig. 2 C and D, the chiral side novel anticancer agents. chains 2a, 4a, 6a, 8a, and 10a are on the same face of the helical The crystal structure of the β-catenin/BCL9/TCF-4 ternary scaffold of sulfono-γ-AApeptides, and thus this face was chosen complex (37) revealed that the helical domain of BCL9 (351- to mimic those critical residues of the BCL9 helical domain. The 374) interacts with a binding groove in β-catenin (Fig. 2 A and B). position map of those residues (Fig. 2E)ontheα-helical scaffold The critical residues of BCL9, R359, L363, L366, I369, and L373, demonstrates that R359, L363, L366, and L373 are almost on the which are on the one face of the BCL9 helix, form both hydro- same line, while I369 is not. A close comparison of helical scaf- philic and hydrophobic contacts with the binding surface of folds of the sulfono-γ-AApeptide and the BCL9 peptide reveals β-catenin. Despite an unambiguous mechanism of action, the that 8b, rather than 8a, could closely mimic I369 (Fig. 2F). As 8b is design of potent intracellular inhibitors to block this PPI remains the sulfonyl side chain, we hypothesized that a methyl sulfonyl a challenge, attributed mainly to the interaction between BCL9 group would be sufficient, because the sulfonyl group sticks out and β-catenin, which is mediated by an ∼25-residue helical seg- more than chiral side chains on helical sulfono-γ-AApeptides.
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