Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins

TY - JOUR

T1 - Identification of compounds with anti-human cytomegalovirus activity that inhibit production of IE2 proteins

AU - Beelontally, Rooksarr

AU - Wilkie, Gavin S.

AU - Lau, Betty

AU - Goodmaker, Charles J.

AU - Ho, Catherine M.K.

AU - Swanson, Chad M.

AU - Deng, Xianming

AU - Wang, Jinhua

AU - Gray, Nathanael S.

AU - Davison, Andrew J.

AU - Strang, Blair L.

PY - 2017/2

Y1 - 2017/2

N2 - Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production.

AB - Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production.

KW - Human cytomegalovirus

KW - Screen

KW - Kinase

KW - Inhibitor

KW - Compound

KW - IE2

U2 - 10.1016/j.antiviral.2016.12.006

DO - 10.1016/j.antiviral.2016.12.006

M3 - Article

SN - 0166-3542

VL - 138

SP - 61

EP - 67

JO - Antiviral Research

JF - Antiviral Research

ER -