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

Date Published: April 5, 2017

Publisher: Public Library of Science

Author(s): Canrong Zhong, Mengyang Xu, Yan Wang, Jun Xu, Yan Yuan, Lindsey Hutt-Fletcher.

http://doi.org/10.1371/journal.ppat.1006289

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.

Partial Text

Kaposi’s sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus type 8 (HHV8), is a member of the γ-herpesviridae subfamily. This virus has been proven to be the etiological agent of Kaposi’s sarcoma (KS) [1]. Almost 100% of KS lesions, regardless of their source or clinic subtype (i.e., classic, AIDS-associated, African endemic, and post transplant KS), are infected with KSHV. KS is the most common malignancy associated with HIV-infection. About 20% of AIDS patients develop KS with most of them (60%) manifesting with oral lesions [2]. Additionally, KSHV is also associated with two lymphoproliferative diseases, namely primary effusion lymphoma (PEL) [3] and multicentric Castleman’s disease (MCD) [4]. Currently there is no definitive cure for KS and other KSHV-associate diseases.

In the current study, we validated APE1 as an effective target for blocking KSHV replication and treating KS and other KSHV-associated malignancies. This study revealed crucial roles of APE1 in KSHV lytic replication, as well as in the development of KS pathogenic features such as cytokine production, angiogenesis and cell invasion. Furthermore, a novel compound was identified that binds to APE1 and blocks its redox function, thereby exhibiting antiviral activity against KSHV and KS pathogenic feature development. The salient features and implication of these findings are as follows.

 

Source:

http://doi.org/10.1371/journal.ppat.1006289

 

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