EBNA1-targeted probe for the imaging and growth inhibition of tumours associated with the Epstein–Barr virus

Jiang, Lijun; Lan, Rongfeng; Huang, Tao; Chan, Chi Fai; Li, Hongguang; Lear, Sam; Zong, Jingyi; Wong, W. Y.; Lee, Magnolia Muk-Lan; Chan, Brandon; Chan, Wai Lun; Lo, Wai Sum; Mak, Nai Ki; Lung, Maria Li; Lung, Hong Lok; Tsao, Sai Wah; Taylor, Graham S.; Bian, Zhao Xiang; Tai, William; Law, Ga Lai; Wong, Wing Tak; Cobb, Steven L.; Wong, Ka Leung

doi:10.1038/s41551-017-0042

Cited by 33 publications

(38 citation statements)

References 24 publications

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“…Given that the N-terminal region of BARF1 is responsible for binding hCSF1 and BARF1-mediated cell growth enhancement and malignant transformation, future studies are required to determine whether agents which target the BARF1 N-terminus specifically are able to block the oncogenic and immunomodulatory functions of the BARF1 protein [ 23 , 24 , 35 ]. Our group has developed EBNA1-specific fluorescent peptide probes (L2P4 and UCNP-P4) which target the EBNA1 dimerization site [ 67 , 68 ]. These probes have proved successful not only in the imaging of tumour xenografts in vivo but also in suppressing the growth of EBV-positive tumour cells in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, BARF1 may constitute a viable candidate for peptide-based therapy. Recently, our group has engineered two EBNA1-specific probes, L2P4 and UCNP-P4 [ 67 , 68 ]. The L2P4 probe contains a water-soluble fluorophore L2 and an EBNA1-binding peptide, P4 (YFMVF-GG-RrRK), incorporated with a nuclear localization sequence (RrRK) moiety, which allows nucleus penetration and localization.…”

Section: The Ebv-encoded Barf1 Proteinmentioning

confidence: 99%

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The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies

Dawson

Lung

et al. 2020

Cancers

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Epstein-Barr virus (EBV) is closely linked to the development of a number of human cancers. EBV-associated malignancies are characterized by a restricted pattern of viral latent protein expression which is sufficient for the virus to both initiate and sustain cell growth and to protect virus-infected cells from immune attack. Expression of these EBV proteins in malignant cells provides an attractive target for therapeutic intervention. Among the viral proteins expressed in the EBV-associated epithelial malignancies, the protein encoded by the BamHI-A rightward frame 1 (BARF1) is of particular interest. BARF1 is a viral oncoprotein selectively expressed in latently infected epithelial cancers, nasopharyngeal carcinoma (NPC) and EBV-positive gastric cancer (EBV-GC). Here, we review the roles of BARF1 in oncogenesis and immunomodulation. We also discuss potential strategies for targeting the BARF1 protein as a novel therapy for EBV-driven epithelial cancers.

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Section: Discussionmentioning

confidence: 99%

Section: The Ebv-encoded Barf1 Proteinmentioning

confidence: 99%

The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies

Dawson

Lung

et al. 2020

Cancers

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“…EBNA-1, which is expressed in all types of EBV-positive cancer cells, represents a specific target for the treatment of EBV-LPDs. A number of inhibitors and vaccines have been developed to target EBNA-1 directly in EBV-positive cancer cells (95–97). MDM2 inhibitors e.g., Nutlin-3a, SAR405838, and JNJ-26854165, or c-Abl kinase inhibitor e.g., Nilotinib, can suppress the growth of lymphomas in EμEBNA-1 transgenic mice via the EBNA-1/MDM2/E2F1 pathway (98).…”

Section: Viral-targeted Therapies Against Ebv-lpdsmentioning

confidence: 99%

Viral-Targeted Strategies Against EBV-Associated Lymphoproliferative Diseases

et al. 2019

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Epstein-Barr virus (EBV) is strongly associated with a spectrum of EBV-associated lymphoproliferative diseases (EBV-LPDs) ranging from post-transplant lymphoproliferative disorder, B cell lymphomas (e.g., endemic Burkitt lymphoma, Hodgkin lymphoma, and diffuse large B cell lymphoma) to NK or T cell lymphoma (e.g., nasal NK/T-cell lymphoma). The virus expresses a number of latent viral proteins which are able to manipulate cell cycle and cell death processes to promote survival of the tumor cells. Several FDA-approved drugs or novel compounds have been shown to induce killing of some of the EBV-LPDs by inhibiting the function of latent viral proteins or activating the viral lytic cycle from latency. Here, we aim to provide an overview on the mechanisms by which EBV employs to drive the pathogenesis of various EBV-LPDs and to maintain the survival of the tumor cells followed by a discussion on the development of viral-targeted strategies based on the understanding of the patho-mechanisms.

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“…The design of JLP 2 represents a step forward, but its profile needs to be optimized including its non-specific cellular localization and its growth-inhibition of Burkitt's lymphoma line. We therefore designed a new series of probes, L 2 P 2 /L 2 P 3 /L 2 P 4 119 - 121 , by incorporating an NLS (RrRK) moiety in the probe skeleton, which enabled nuclear localization and targeted nuclear EBNA1 ( Figure 7 , lower panel) 48 , 122 . Molecular dynamics simulations suggested an unexpected role of RrRK, which formed salt bridges among several residues in the aspartate-rich tail of EBNA1 and thus contributed to stabilization of the NLS-containing probe-EBNA1 complex.…”

Section: Strategies For Blocking Ebna1 Expression or Ebna1-dependent mentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

EBNA1-targeted inhibitors: Novel approaches for the treatment of Epstein-Barr virus-associated cancers

et al. 2018

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Epstein-Barr virus (EBV) infects more than 90% of humans worldwide and establishes lifelong latent infection in the hosts. It is closely associated with endemic forms of a wide range of human cancers and directly contributes to the formation of some. Despite its critical role in cancer development, no EBV- or EBV latent protein-targeted therapy is available. The EBV-encoded latent protein, Epstein-Barr nuclear antigen 1 (EBNA1), is expressed in all EBV-associated tumors and acts as the only latent protein in some of these tumors. This versatile protein functions in the maintenance, replication, and segregation of the EBV genome and can therefore serve as an attractive therapeutic target to treat EBV-associated cancers. In the last decades, efforts have been made for designing specific EBNA1 inhibitors to decrease EBNA1 expression or interfere with EBNA1-dependent functions. In this review, we will briefly introduce the salient features of EBNA1, summarize its functional domains, and focus on the recent developments in the identification and design of EBNA1 inhibitors related to various EBNA1 domains as well as discuss their comparative merits.

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EBNA1-targeted probe for the imaging and growth inhibition of tumours associated with the Epstein–Barr virus

Abstract: EBNA1-targeted probe for the imaging and growth inhibition of EBNA1-targeted probe for the imaging and growth inhibition of tumours associated with the Epstein-Barr virus tumours associated with the Epstein-Barr virus

Cited by 33 publications

References 24 publications

The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies

The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies

Viral-Targeted Strategies Against EBV-Associated Lymphoproliferative Diseases

EBNA1-targeted inhibitors: Novel approaches for the treatment of Epstein-Barr virus-associated cancers

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