Development of potent inhibitors of the coxsackievirus 3C protease

Eui Seung Lee; Won Gil Lee; Soo Hyeon Yun; Seong Hwan Rho; Isak Im; Sung Tae Yang; Saravanan Sellamuthu; Yong Jae Lee; Sun Jae Kwon; Ohkmae K. Park; Eun Seok Jeon; Woo Jin Park; Yong Chul Kim

doi:10.1016/j.bbrc.2007.03.208

Development of potent inhibitors of the coxsackievirus 3C protease

Eui Seung Lee, Won Gil Lee, Soo Hyeon Yun, Seong Hwan Rho, Isak Im, Sung Tae Yang, Saravanan Sellamuthu, Yong Jae Lee, Sun Jae Kwon, Ohkmae K. Park, Eun Seok Jeon, Woo Jin Park, Yong Chul Kim

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

Abstract

Coxsackievirus B3 (CVB3) 3C protease (3CP) plays essential roles in the viral replication cycle, and therefore, provides an attractive therapeutic target for treatment of human diseases caused by CVB3 infection. CVB3 3CP and human rhinovirus (HRV) 3CP have a high degree of amino acid sequence similarity. Comparative modeling of these two 3CPs revealed one prominent distinction; an Asn residue delineating the S2′ pocket in HRV 3CP is replaced by a Tyr residue in CVB3 3CP. AG7088, a potent inhibitor of HRV 3CP, was modified by substitution of the ethyl group at the P2′ position with various hydrophobic aromatic rings that are predicted to interact preferentially with the Tyr residue in the S2′ pocket of CVB3 3CP. The resulting derivatives showed dramatically increased inhibitory activities against CVB3 3CP. In addition, one of the derivatives effectively inhibited the CVB3 proliferation in vitro.

Original language	English
Pages (from-to)	7-11
Number of pages	5
Journal	Biochemical and biophysical research communications
Volume	358
Issue number	1
DOIs	https://doi.org/10.1016/j.bbrc.2007.03.208
Publication status	Published - 2007 Jun 22

Keywords

3C protease
Coaxsackievirus
Inhibitor

ASJC Scopus subject areas

Biophysics
Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbrc.2007.03.208

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title = "Development of potent inhibitors of the coxsackievirus 3C protease",

abstract = "Coxsackievirus B3 (CVB3) 3C protease (3CP) plays essential roles in the viral replication cycle, and therefore, provides an attractive therapeutic target for treatment of human diseases caused by CVB3 infection. CVB3 3CP and human rhinovirus (HRV) 3CP have a high degree of amino acid sequence similarity. Comparative modeling of these two 3CPs revealed one prominent distinction; an Asn residue delineating the S2′ pocket in HRV 3CP is replaced by a Tyr residue in CVB3 3CP. AG7088, a potent inhibitor of HRV 3CP, was modified by substitution of the ethyl group at the P2′ position with various hydrophobic aromatic rings that are predicted to interact preferentially with the Tyr residue in the S2′ pocket of CVB3 3CP. The resulting derivatives showed dramatically increased inhibitory activities against CVB3 3CP. In addition, one of the derivatives effectively inhibited the CVB3 proliferation in vitro.",

keywords = "3C protease, Coaxsackievirus, Inhibitor",

author = "Lee, {Eui Seung} and Lee, {Won Gil} and Yun, {Soo Hyeon} and Rho, {Seong Hwan} and Isak Im and Yang, {Sung Tae} and Saravanan Sellamuthu and Lee, {Yong Jae} and Kwon, {Sun Jae} and Park, {Ohkmae K.} and Jeon, {Eun Seok} and Park, {Woo Jin} and Kim, {Yong Chul}",

note = "Funding Information: During this work, W.J.P. was supported by a GRL Grant (M6-0605-00-0001) from the Ministry of Science and Technology, Korea, YCK was supported by a grant of the Korea Health 21 R&D Project, from the Ministry of Health & Welfare, Republic of Korea (Grant No. A040042), and OKP was supported by a grant from the Plant Signaling Network Research Center funded by the Korea Science and Engineering Foundation.",

year = "2007",

month = jun,

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doi = "10.1016/j.bbrc.2007.03.208",

language = "English",

volume = "358",

pages = "7--11",

journal = "Biochemical and Biophysical Research Communications",

issn = "0006-291X",

publisher = "Academic Press Inc.",

number = "1",

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TY - JOUR

T1 - Development of potent inhibitors of the coxsackievirus 3C protease

AU - Lee, Eui Seung

AU - Lee, Won Gil

AU - Yun, Soo Hyeon

AU - Rho, Seong Hwan

AU - Im, Isak

AU - Yang, Sung Tae

AU - Sellamuthu, Saravanan

AU - Lee, Yong Jae

AU - Kwon, Sun Jae

AU - Park, Ohkmae K.

AU - Jeon, Eun Seok

AU - Park, Woo Jin

AU - Kim, Yong Chul

N1 - Funding Information: During this work, W.J.P. was supported by a GRL Grant (M6-0605-00-0001) from the Ministry of Science and Technology, Korea, YCK was supported by a grant of the Korea Health 21 R&D Project, from the Ministry of Health & Welfare, Republic of Korea (Grant No. A040042), and OKP was supported by a grant from the Plant Signaling Network Research Center funded by the Korea Science and Engineering Foundation.

PY - 2007/6/22

Y1 - 2007/6/22

N2 - Coxsackievirus B3 (CVB3) 3C protease (3CP) plays essential roles in the viral replication cycle, and therefore, provides an attractive therapeutic target for treatment of human diseases caused by CVB3 infection. CVB3 3CP and human rhinovirus (HRV) 3CP have a high degree of amino acid sequence similarity. Comparative modeling of these two 3CPs revealed one prominent distinction; an Asn residue delineating the S2′ pocket in HRV 3CP is replaced by a Tyr residue in CVB3 3CP. AG7088, a potent inhibitor of HRV 3CP, was modified by substitution of the ethyl group at the P2′ position with various hydrophobic aromatic rings that are predicted to interact preferentially with the Tyr residue in the S2′ pocket of CVB3 3CP. The resulting derivatives showed dramatically increased inhibitory activities against CVB3 3CP. In addition, one of the derivatives effectively inhibited the CVB3 proliferation in vitro.

AB - Coxsackievirus B3 (CVB3) 3C protease (3CP) plays essential roles in the viral replication cycle, and therefore, provides an attractive therapeutic target for treatment of human diseases caused by CVB3 infection. CVB3 3CP and human rhinovirus (HRV) 3CP have a high degree of amino acid sequence similarity. Comparative modeling of these two 3CPs revealed one prominent distinction; an Asn residue delineating the S2′ pocket in HRV 3CP is replaced by a Tyr residue in CVB3 3CP. AG7088, a potent inhibitor of HRV 3CP, was modified by substitution of the ethyl group at the P2′ position with various hydrophobic aromatic rings that are predicted to interact preferentially with the Tyr residue in the S2′ pocket of CVB3 3CP. The resulting derivatives showed dramatically increased inhibitory activities against CVB3 3CP. In addition, one of the derivatives effectively inhibited the CVB3 proliferation in vitro.

KW - 3C protease

KW - Coaxsackievirus

KW - Inhibitor

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Development of potent inhibitors of the coxsackievirus 3C protease

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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