Wei Wang1,2, Cuijing Xu1, Jianqiang Zhang1, Jinpeng Wang1, Rilei Yu1,2, Dongping Wang1, Ruijuan Yin1, Wenmiao Li1, Tao Jiang1,2. 1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China. 2. Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
Abstract
BACKGROUND AND PURPOSE: The worldwide prevalence of herpes simplex virus (HSV) and shortage of efficient therapeutic strategies to counteract it are global concerns. In terms of treatment, the widely utilized anti-HSV drugs such as acyclovir have serious limitations, for example, drug resistance and side effects. Here, we have identified the guanidine-modified (E,E)-4,6-bis(styryl)-pyrimidine (BS-pyrimidine) derivative compound 5d as an inhibitor of HSV and further elucidated the anti-HSV mechanisms of compound 5d both in vitro and in vivo. EXPERIMENTAL APPROACH: Cytopathic effect inhibition assay, plaque assay, and immunofluorescence assay were used to evaluate the anti-HSV effects of compound 5d in vitro. Membrane fusion assays, immunofluorescence assays, Western blotting assays, and pull-down assays were used to explore the anti-HSV mechanisms of compound 5d. HSV-1-infected mice, combined with haematoxylin-eosin staining and quantitative RT-PCR, were used to study the anti-HSV effects of compound 5d in vivo. KEY RESULTS: The guanidine-modified compound 5d rather than the un-modified compound 3a effectively inhibited both HSV-1 and HSV-2 multiplication in different cell lines, more effectively than acyclovir. Compound 5d may block virus binding and post-binding processes such as membrane fusion, by targeting virus gB protein. In addition, compound 5d may also down-regulate the cellular PI3K/Akt signalling pathway to interfere with HSV replication. Treatment with compound 5d also markedly improved survival and decreased viral titres in HSV-infected mice. CONCLUSIONS AND IMPLICATIONS: Thus, the guanidine-modified BS-pyrimidine derivatives have the potential to be developed into novel anti-HSV agents targeting both virus gB protein and cellular PI3K/Akt signalling pathways.
BACKGROUND AND PURPOSE: The worldwide prevalence of herpes simplex virus (HSV) and shortage of efficient therapeutic strategies to counteract it are global concerns. In terms of treatment, the widely utilized anti-HSV drugs such as acyclovir have serious limitations, for example, drug resistance and side effects. Here, we have identified the guanidine-modified (E,E)-4,6-bis(styryl)-pyrimidine (BS-pyrimidine) derivative compound 5d as an inhibitor of HSV and further elucidated the anti-HSV mechanisms of compound 5d both in vitro and in vivo. EXPERIMENTAL APPROACH: Cytopathic effect inhibition assay, plaque assay, and immunofluorescence assay were used to evaluate the anti-HSV effects of compound 5d in vitro. Membrane fusion assays, immunofluorescence assays, Western blotting assays, and pull-down assays were used to explore the anti-HSV mechanisms of compound 5d. HSV-1-infected mice, combined with haematoxylin-eosin staining and quantitative RT-PCR, were used to study the anti-HSV effects of compound 5d in vivo. KEY RESULTS: The guanidine-modified compound 5d rather than the un-modified compound 3a effectively inhibited both HSV-1 and HSV-2 multiplication in different cell lines, more effectively than acyclovir. Compound 5d may block virus binding and post-binding processes such as membrane fusion, by targeting virus gB protein. In addition, compound 5d may also down-regulate the cellular PI3K/Akt signalling pathway to interfere with HSV replication. Treatment with compound 5d also markedly improved survival and decreased viral titres in HSV-infected mice. CONCLUSIONS AND IMPLICATIONS: Thus, the guanidine-modified BS-pyrimidine derivatives have the potential to be developed into novel anti-HSV agents targeting both virus gB protein and cellular PI3K/Akt signalling pathways.
Authors: Brett Lomenick; Rui Hao; Nao Jonai; Randall M Chin; Mariam Aghajan; Sarah Warburton; Jianing Wang; Raymond P Wu; Fernando Gomez; Joseph A Loo; James A Wohlschlegel; Thomas M Vondriska; Jerry Pelletier; Harvey R Herschman; Jon Clardy; Catherine F Clarke; Jing Huang Journal: Proc Natl Acad Sci U S A Date: 2009-12-07 Impact factor: 11.205
Authors: Simon D Harding; Joanna L Sharman; Elena Faccenda; Chris Southan; Adam J Pawson; Sam Ireland; Alasdair J G Gray; Liam Bruce; Stephen P H Alexander; Stephen Anderton; Clare Bryant; Anthony P Davenport; Christian Doerig; Doriano Fabbro; Francesca Levi-Schaffer; Michael Spedding; Jamie A Davies Journal: Nucleic Acids Res Date: 2018-01-04 Impact factor: 16.971