title: An APE1 inhibitor reveals critical roles of the redox function of APE1 in KSHV replication and pathogenic phenotypes.
abstract: APE1 is a multifunctional protein with a DNA base excision repair function in its C-terminal domain and a redox activity in its N-terminal domain. The redox function of APE1 converts certain transcription factors from inactive oxidized to active reduced forms. Given that among the APE1-regulated transcription factors many are critical for KSHV replication and pathogenesis, we investigated whether inhibition of APE1 redox function blocks KSHV replication and Kaposi's sarcoma (KS) phenotypes. With an shRNA-mediated silencing approach and a known APE-1 redox inhibitor, we demonstrated that APE1 redox function is indeed required for KSHV replication as well as KSHV-induced angiogenesis, validating APE1 as a therapeutic target for KSHV-associated diseases. A ligand-based virtual screening yielded a small molecular compound, C10, which is proven to bind to APE1. C10 exhibits low cytotoxicity but efficiently inhibits KSHV lytic replication (EC50 of 0.16 μM and selective index of 165) and KSHV-mediated pathogenic phenotypes including cytokine production, angiogenesis and cell invasion, demonstrating its potential to become an effective drug for treatment of KS.
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.|Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Canrong
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Xu
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.|Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.|Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, China.|Department of Microbiology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Yan
authors.identifier: http://orcid.org/0000-0002-3064-1955
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects* / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000187:drug effects* / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010084:Oxidation-Reduction / Q000187:drug effects*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D034741:RNA, Small Interfering; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase