An APE1 inhibitor reveals critical roles of the redox function of APE1 in KSHV replication and pathogenic phenotypes

PLoS Pathogens

Yan Yuan¹  Canrong Zhong²  Jun Xu²  Mengyang Xu³  Yan Wang⁴ 

[1] Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, China;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;Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China

关键词: Oxidation-reduction reactions;    Angiogenesis;    DNA replication;    Viral replication;    Virions;    Cytokines;    Kaposi's sarcoma-associated herpesvirus;    Transcription factors;   

DOI  :  10.1371/journal.ppat.1006289

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY