Antiviral Mechanisms of Pyridyl Imidazolidinones and Pyrazolo[3,4-D]Pyrimidines, Two Novel and Potent Inhibitors for Enteroviruses (I)

Enterovirus epidemics occurred every year during spring/summer time in Taiwan due to a number of factors, including warm temperature, high humidity and dense population. The infection can be accompanied by severe complications in children, such as encephalitis, myocarditis, and even death. It is therefore important and urgent to control and prevent enterovirus infection in Taiwan. Infectious disease due to enterovirus is one of the major topics for investigation in the National Research Program for Genomic Medicine. In this program project, we aim to study the functional roles of viral and host cellular factors in enterovirus infection, which would help in developing the anti-enteroviral agents, as well as strategies for control and treatment of the associated diseases. The program project contains five component projects. The principle investigators include clinical physician, virologists, biochemists and molecular biologists. The PIs have been participating in enterovirus research since 1998, in which an enterovirus 71 outbreak occurred in Taiwan. Our major achievements include outbreak investigations, diagnostic kits development, revealing the transmission pathways, discovery of two novel anti-enteroviral agents and other basic virological researches. Component project #1 (by Dr. Shin-Ru Shih) has been studying the antiviral mechanism of “Z” (pyridyl imidazolidinone) and “M” (pyrazolo[3,4-d]pyrimidines) compounds, two novel and potent inhibitors for enteroviruses, and use them as probe to investigate the viral-host cell interactions. Component project #2 (by Dr. Hsiu-Ming Shih) has been analyzing the functions of enterovirus 71 protease 2A and 3C in regulating protein sumoylation, which would lead to more understanding to the role of viral protease - an important molecular target for drug discovery. Component project #3 (by Dr. Luan-Yin Chang) has been studying the host factors causing severe complications in patients, which can help uncovering the pathogenesis of enterovirus infection. Project #4 (by Dr. Jyh-Lyh Juang) has been investigating the pathway of apoptosis in enterovirus-infected neural cells, which would be important to understand how virus triggers the cellular signaling. In the past few years, we had successfully built an infrastructure for collaboration upon enterovirus researches, such as to hold regular meetings, to share materials, and to exchange knowledge and experiences. For the past year, this program project got the following major results: (1) The molecular target for “M” compound seems to be 3D polymerase according the sequence analysis of M-resistant viruses. (2) Sumoylation of PML could be down-regulated by the expression of 2A or 3C protease, indicating EV71 infection may interfere with PML-NBs formation. (3) EV71 cases with pulmonary edema had significantly lower cellular γ-interferon (p=0.04), lower cellular 8 interleukin-1　, lower cellular interleukin-6, lower cellular tumor necrosis factor-　 response), and lower cellular macrophage inflammatory protein-1　response as compared to other cases. (4) EV71 infection elevated Cdk5-tyr15 phosphorylation level. In vitro kinase assay showed that Cdk5 kinase activity was enhanced by the virus infection. Cdk5 kinase inhibitors blockade of Cdk5 activation during EV71 infection.

Project ID:PA9506-0071
External Project ID:NSC95-3112-B182-007