A Small Molecule That Inhibits OGT Activity in Cells

Ortiz‐Meoz, Rodrigo F.; Jiang, Jiaoyang; Lazarus, Michael B.; Orman, Marina; Janetzko, John; Fan, Chenguang; Duveau, Damien Y.; Tan, Zhi Wei; Thomas, Craig J.; Walker, Suzanne

doi:10.1021/acschembio.5b00004

Cited by 225 publications

(228 citation statements)

References 44 publications

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“…Despite recent progress [10,11], very few such non-substrate-like GT inhibitors are currently available, in stark contrast to other enzyme classes of similar size and biological importance (e.g. kinases, proteases).…”

Section: Introductionmentioning

confidence: 99%

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Smith

Vivoli

et al. 2017

Bioorganic & Medicinal Chemistry

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. Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorganic and Medicinal Chemistry, 25(12), 3182-3194. https://doi.org/10.1016/j.bmc.2017.04.006Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rightsCopyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights.•Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.•You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policyIf you believe that this document breaches copyright please contact librarypure@kcl.ac.uk providing details, and we will remove access to the work immediately and investigate your claim. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.-1 - data reveals that non-catalytic cysteines are a common motif in the active site of many bacterial glycosyltransferases. Our results can therefore serve as a blueprint for the rational design of non-substrate-like, covalent inhibitors against a broad range of other bacterial glycosyltransferases.-3 -

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Section: Introductionmentioning

confidence: 99%

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Smith

Vivoli

et al. 2017

Bioorganic & Medicinal Chemistry

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“…High‐throughput screening has been pursued to deliver hits that can be improved upon 5b,5d. These leads, however, show modest cellular activity and limited solubility 5b.…”

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confidence: 99%

“…These leads, however, show modest cellular activity and limited solubility 5b. They also exhibit off‐target cellular toxicity 5b. Another approach5c has been to generate a GlcNAc analogue, 2‐acetamido‐2‐deoxy‐5‐thio‐α‐ d ‐glucopyranose (5SGlcNAc, 3 ), which in its per‐O‐acetylated form (Ac 4 5SGlcNAc, 3 ‐OAc) can diffuse across the plasma membrane.…”

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confidence: 99%

“…Notably, others have shown that Ac 4 5SGlcNAc ( 3 ‐OAc) appears to be able to inhibit other glycosyltransferases in cell lines 5b. We found, however, by lectin blot assessment that 12 induced no apparent changes in other forms of protein glycosylation in all tissues tested (Figure S7) even at a dose of 300 mg kg −1 after 48 h, which is consistent with a recent report on the use of the parent compound Ac 4 5SGlcNAc ( 3 ‐OAc) in cells 10…”

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confidence: 99%

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Metabolic Inhibitors of O‐GlcNAc Transferase That Act In Vivo Implicate Decreased O‐GlcNAc Levels in Leptin‐Mediated Nutrient Sensing

et al. 2018

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O‐Linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N‐acetylglucosamine (O‐GlcNAc) residues is catalyzed by O‐GlcNAc transferase (OGT). O‐GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Herein, we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5‐thiosugar analogues of N‐acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N‐acetylglucosamine‐6‐phosphate de‐N‐acetylase (NAGA), to generate a common OGT inhibitor within cells. We show that of these inhibitors, 2‐deoxy‐2‐N‐hexanamide‐5‐thio‐d‐glucopyranoside (5SGlcNHex) acts in vivo to induce dose‐ and time‐dependent decreases in O‐GlcNAc levels in various tissues. Decreased O‐GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of the transcription factor Sp1 and the satiety‐inducing hormone leptin, thus revealing a link between decreased O‐GlcNAc levels and nutrient sensing in peripheral tissues of mammals.

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“…Because HSV relies on the cellular transcriptional machinery for expression of its genes, we determined if OGT plays a role during HSV infection. To address this question, we utilized a recently developed small molecule inhibitor of OGT, OSMI-1, which was shown to specifically inhibit the catalytic activity of OGT, decrease global O-GlcNAcylation, and inhibit O-GlcNAc modification of known OGT substrates (19). We observed that blocking OGT's catalytic activity significantly decreases replication of HSV-1, HSV-2, and cytomegalovirus.…”

mentioning

confidence: 99%

Inhibition of O-Linked N -Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus

Angelova

Ortiz‐Meoz

Walker

et al. 2015

J Virol

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O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential cellular enzyme that posttranslationally modifies nuclear and cytoplasmic proteins via O-linked addition of a single N-acetylglucosamine (GlcNAc) moiety. Among the many targets of OGT is host cell factor 1 (HCF-1), a transcriptional regulator that is required for transactivation of the immediate-early genes of herpes simplex virus (HSV). HCF-1 is synthesized as a large precursor that is proteolytically cleaved by OGT, which may regulate its biological function. In this study, we tested whether inhibition of the enzymatic activity of OGT with a small molecule inhibitor, OSMI-1, affects initiation of HSV immediate-early gene expression and viral replication. We found that inhibiting OGT's enzymatic activity significantly decreased HSV replication. The major effect of the inhibitor occurred late in the viral replication cycle, when it reduced the levels of late proteins and inhibited capsid formation. However, depleting OGT levels with small interfering RNA (siRNA) reduced the expression of HSV immediate-early genes, in addition to reducing viral yields. In this study, we identified OGT as a novel cellular factor involved in HSV replication. Our results obtained using a small molecule inhibitor and siRNA depletion suggest that OGT's glycosylation and scaffolding functions play distinct roles in the replication cycle of HSV. IMPORTANCE Antiviral agents can target viral or host gene products essential for viral replication. O-GlcNAc transferase (OGT)is an important cellular enzyme that catalyzes the posttranslational addition of GlcNAc sugar residues to hundreds of nuclear and cytoplasmic proteins, and this modification regulates their activity and function. Some of the known OGT targets are cellular proteins that are critical for the expression of herpes simplex virus (HSV) genes, suggesting a role for OGT in the replication cycle of HSV. In this study, we found that OGT is required for efficient expression of viral genes and for assembly of new virions. Thus, we identify OGT as a novel host factor involved in the replication of HSV and a potential target for antiviral therapy. Herpes simplex virus (HSV) causes a variety of infections that can lead to considerable morbidity and mortality in immunocompromised patients and neonates (1). Lytic replication of HSV occurs in a highly regulated fashion with sequential expression of immediate-early (IE), early (E), and late (L) viral genes (1). IE gene transcription occurs in the absence of de novo viral protein synthesis and requires the viral VP16 tegument protein, which, in infected cells, forms a complex with two host transcription factors: octamer-binding protein 1 (Oct-1) and the transcriptional coregulator host cell factor 1 (HCF-1) (2-5). The VP16 -Oct-1-HCF-1 multiprotein complex binds to conserved core elements on IE gene promoters and recruits cellular transcription and chromatin-modifying factors to initiate high levels of viral gene expression (6-8). HCF-1 is essential for VP16-me...

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A Small Molecule That Inhibits OGT Activity in Cells

Cited by 225 publications

References 44 publications

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Covalent inhibitors of LgtC: A blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases

Metabolic Inhibitors of O‐GlcNAc Transferase That Act In Vivo Implicate Decreased O‐GlcNAc Levels in Leptin‐Mediated Nutrient Sensing

Inhibition of O-Linked N -Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus

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