國家衛生研究院 NHRI:Item 3990099045/9668

NHRI > Institute of Biotechnology and Pharmaceutical Research > Teng-Kuang Yeh > Periodical Articles > Item 3990099045/9668

Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/9668

Title:	In vitro and in vivo studies of a potent capsid-binding inhibitor of enterovirus 71
Authors:	Ho, JY;Chern, JH;Hsieh, CF;Liu, ST;Liu, CJ;Wang, YS;Kuo, TW;Hsu, SJ;Yeh, TK;Shih, SR;Hsieh, PW;Chiu, CH;Horng, JT
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	OBJECTIVES: Enterovirus 71 (EV-A71) is an important pathogen that can cause severe neurological symptoms and even death. Our aim was to identify potent anti-EV-A71 compounds and study their underlying mechanisms and in vivo activity. METHODS: We identified a potent imidazolidinone derivative (abbreviated to PR66) as an inhibitor of EV-A71 infection from the screening of compounds and subsequent structure-based modification. Time-course treatments and resistant virus selection of PR66 were employed to study the mode of mechanism of PR66. In vivo activity of PR66 was tested in the ICR strain of new-born mice challenged with EV-A71/4643/MP4. RESULTS: PR66 could impede the uncoating process during viral infection via interaction with capsid protein VP1, as shown by a resistant virus selection assay. Using site-directed mutagenesis, we confirmed that a change from valine to phenylalanine in the 179th amino acid residue of the cDNA-derived resistant virus resulted in resistance to PR66. PR66 increased the virion stability of WT viruses, but not the PR66-resistant mutant, in a particle stability thermal release assay. We further showed that PR66 had excellent anti-EV-A71 activity in an in vivo mouse model of disease, with a dose-dependent increase in survival rate and in protection against virus-induced hind-limb paralysis following oral or intraperitoneal administration. This was associated with reductions of viral titres in brain and muscle tissues. CONCLUSIONS: We demonstrated here for the first time that an imidazolidinone derivative (PR66) could protect against EV-A71-induced neurological symptoms in vivo by suppressing EV-A71 replication. This involved binding to and restricting viral uncoating.
Date:	2016-07
Relation:	Journal of Antimicrobial Chemotherapy. 2016 Jul;71(7):1922-1932.
Link to:	http://dx.doi.org/10.1093/jac/dkw101
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0305-7453&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000383246000023
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84979072540
Appears in Collections:	[Teng-Kuang Yeh] Periodical Articles [Jyh-Haur Chern] Periodical Articles

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