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Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth.
J Med Chem. 2018 Aug 09; 61(15):6674-6684.JM

Abstract

Epstein-Barr virus (EBV) establishes latent infection and is associated with several types of lymphomas and carcinomas. EBV nuclear antigen 1 (EBNA1) is expressed in all EBV-positive tumor cells. EBNA1 binds to the origin of virus plasmid replication (OriP) on the EBV episome to initiate virus DNA replication and regulates virus gene expression as a transcriptional activator. In this study, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst 33258 conjugate named EIP-2 (2), which specifically binds to the OriP region with high affinity, to interrupt EBNA1-OriP binding in vitro and in vivo. By eradicating the EBV episome in EBV-positive cells, compound 2 selectively inhibited EBV-positive cell proliferation. Moreover, the injection of 2 significantly suppressed tumor growth in the mice xenograft tumor model. These findings demonstrate that compound 2 is a potential therapeutic candidate for the treatment of EBV-associated tumors.

Authors+Show Affiliations

Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology , Shenzhen Institutes of Advanced Technology , Shenzhen , Guangdong 518055 , China. Shenzhen College of Advanced Technology , University of Chinese Academy of Sciences , Shenzhen , Guangdong 518055 , China.Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology , Shenzhen Institutes of Advanced Technology , Shenzhen , Guangdong 518055 , China.Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology , Shenzhen Institutes of Advanced Technology , Shenzhen , Guangdong 518055 , China.Shenzhen Laboratory of Antibody Engineering, Institute of Biomedicine and Biotechnology , Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen , Guangdong 518055 , China.Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology , Shenzhen Institutes of Advanced Technology , Shenzhen , Guangdong 518055 , China.Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology , Shenzhen Institutes of Advanced Technology , Shenzhen , Guangdong 518055 , China.Shenzhen Laboratory of Antibody Engineering, Institute of Biomedicine and Biotechnology , Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen , Guangdong 518055 , China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30008213

Citation

Cheng, Zhehong, et al. "Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth." Journal of Medicinal Chemistry, vol. 61, no. 15, 2018, pp. 6674-6684.
Cheng Z, Wang W, Wu C, et al. Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth. J Med Chem. 2018;61(15):6674-6684.
Cheng, Z., Wang, W., Wu, C., Zou, X., Fang, L., Su, W., & Wang, P. (2018). Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth. Journal of Medicinal Chemistry, 61(15), 6674-6684. https://doi.org/10.1021/acs.jmedchem.8b00496
Cheng Z, et al. Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth. J Med Chem. 2018 Aug 9;61(15):6674-6684. PubMed PMID: 30008213.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel Pyrrole-Imidazole Polyamide Hoechst Conjugate Suppresses Epstein-Barr Virus Replication and Virus-Positive Tumor Growth. AU - Cheng,Zhehong, AU - Wang,Wei, AU - Wu,Chunlei, AU - Zou,Xiaohua, AU - Fang,Lijing, AU - Su,Wu, AU - Wang,Pu, Y1 - 2018/07/30/ PY - 2018/7/17/pubmed PY - 2019/6/19/medline PY - 2018/7/17/entrez SP - 6674 EP - 6684 JF - Journal of medicinal chemistry JO - J Med Chem VL - 61 IS - 15 N2 - Epstein-Barr virus (EBV) establishes latent infection and is associated with several types of lymphomas and carcinomas. EBV nuclear antigen 1 (EBNA1) is expressed in all EBV-positive tumor cells. EBNA1 binds to the origin of virus plasmid replication (OriP) on the EBV episome to initiate virus DNA replication and regulates virus gene expression as a transcriptional activator. In this study, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst 33258 conjugate named EIP-2 (2), which specifically binds to the OriP region with high affinity, to interrupt EBNA1-OriP binding in vitro and in vivo. By eradicating the EBV episome in EBV-positive cells, compound 2 selectively inhibited EBV-positive cell proliferation. Moreover, the injection of 2 significantly suppressed tumor growth in the mice xenograft tumor model. These findings demonstrate that compound 2 is a potential therapeutic candidate for the treatment of EBV-associated tumors. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/30008213/Novel_Pyrrole_Imidazole_Polyamide_Hoechst_Conjugate_Suppresses_Epstein_Barr_Virus_Replication_and_Virus_Positive_Tumor_Growth_ L2 - https://doi.org/10.1021/acs.jmedchem.8b00496 DB - PRIME DP - Unbound Medicine ER -