Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo.
Herpes simplex virus (HSV) is a common human pathogen that causes a variety of diseases, including oral-labial, genital lesions and life-threatening encephalitis. The antiviral nucleoside analogues such as acyclovir are currently used in anti-HSV therapies; however, clinical overuse of these drugs has led to the emergence of drug-resistant viral strains. Hence, there is an urgent need to develop new anti-HSV agents.



To identify novel anti-HSV-1 compounds, we screened the LOPAC small scale library of 1280 bioactive compounds to identify inhibitors of HSV-1-induced necroptosis. Further experiments including western blot analysis, Q-PCR analysis and immunohistochemistry were performed to explore the antiviral mechanism of the compounds.



Here, we identified PHA767491 as a new inhibitor of HSV. PHA767491 potently blocked the proliferation of HSV in cells, as well as HSV induced cell death. Further, we found that PHA767491 strongly inhibited HSV infection post viral entry. Moreover, PHA767491 reduced the expression of viral genes required for DNA synthesis including UL30/42 DNA polymerase and UL5/8/52 helicase-primase complex. The essential immediate early (IE) genes such as ICP4 and ICP27 are critical for the expression of the early and late genes. Of note, PHA767491 inhibited the expression of all IE genes of both HSV-1 and HSV-2. Importantly, PHA767491 reduced viral titers in the tissues from the mice infected with HSV-1. Consistently, immunohistochemistry analysis showed that PHA767491 dramatically attenuated expression of viral protein gB in the livers.



Taken together, PHA767491 has potent anti-HSV activity by inhibiting viral replication both in vitro and in mouse model. Thus, PHA767491 could be a promising agent for the development of new anti-HSV therapy.
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Jue
J
Hou
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Zili
Z
Zhang
Department of emergency medicine, First Affiliated Hospital, Soochow University, 1 Shizhi Rd, Suzhou, Jiangsu, China.
Qiang
Q
Huang
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Jun
J
Yan
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Xiaohu
X
Zhang
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Xiaoliang
X
Yu
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Soochow University, Suzhou, China.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
Guihua
G
Tan
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
Chunfu
C
Zheng
Department of emergency medicine, First Affiliated Hospital, Soochow University, 1 Shizhi Rd, Suzhou, Jiangsu, China. sz_xf@suda.edu.cn.
Feng
F
Xu
Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, Soochow University, Suzhou, China. hesudan@suda.edu.cn.|Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China. hesudan@suda.edu.cn.
Sudan
S
He
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D015967:Gene Expression Regulation, Viral; D006561:Herpes Simplex / Q000188:drug therapy* / Q000821:virology*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D010881:Piperidones / Q000494:pharmacology* / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; C531237:PHA 767491; D010881:Piperidones; D011758:Pyrroles; D014764:Viral Proteins
Anti-HSV; HSV; Immediate early gene; PHA767491; Viral replication