Screening of Anti-HSV Agents and Study of Their Antiviral Mechanisms
Date Issued
2004
Date
2004
Author(s)
Su, Chun-Ting
DOI
zh-TW
Abstract
Herpes Simplex Virus (HSV) types 1 and 2 infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. After primary infections, HSV can establish persistent infection in nervous system and may reactivate intermittently upon appropriate stimuli. Because of the wide popularity, high ability to transmit and the difficulty to develop prophylactic vaccines, development of chemotherapy is comparatively important. To date, the most widely used and successful chemotherapy are nucleoside analogue agents such as acyclovir (ACV), which inhibits viral DNA polymerase after being phosphorylated by HSV thymidine kinase (TK). However, development of nucleoside analogue-resistant HSV strains has been reported in immunocompromised individuals. Thus, there is a need to develop novel anti-HSV agents to substitute for or to complement conventional anti-HSV chemotherapy. In this study we first screened a total of 960 candidate chemicals for their antiviral activity. Seventy-three of these candidate chemicals were further confirmed to have definite antiviral activity by plaque reduction assay. Among these 73 chemicals, 14 have a 50% effective concentration (EC50) lower than 1 μM. The cytotoxicity concentration (CC50) of these chemicals was subsequently determined by MTT assay and the selective index (SI) for each chemical was thus calculated. One potential drug, 12-2 8G, with SI=17 was further analyzed. By in vitro assay, HSV-1 replication was not significantly inhibited when 12-2 8G was added at viral entry, virus pretreatment or cell pretreatment. In the time-of-addition assay, 12-2 8G was shown to inhibit HSV-1 replication between 6 and 12 hours after infection. It is likely that 12-2 8G block HSV-1 infection at early or late stage. However, there was no interaction between 12-2 8G and ACV based on isobologram analysis. 12-2 8G did not significantly inhibit HSV DNA replication. We will perform time-of-addition assay and RT-PCR to further clarify the target(s) of 12-2 8G. Such information will be helpful in the development and designing of antiviral agents in the future.
Subjects
單純皰疹病毒
抗病毒藥物
HSV
antiviral drug
SDGs
Type
other
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