Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease

Vishnu C. Damalanka; Yunjeong Kim; Kevin R. Alliston; Pathum M. Weerawarna; Anushka C. Galasiti Kankanamalage; Gerald H. Lushington; Nurjahan Mehzabeen; Kevin P. Battaile; Scott Lovell; Kyeong Ok Chang; William C. Groutas

doi:10.1021/acs.jmedchem.5b01464

Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease

Vishnu C. Damalanka, Yunjeong Kim, Kevin R. Alliston, Pathum M. Weerawarna, Anushka C. Galasiti Kankanamalage, Gerald H. Lushington, Nurjahan Mehzabeen, Kevin P. Battaile, Scott Lovell, Kyeong Ok Chang, William C. Groutas

Department of Biochemistry & Molecular Biophysics

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

24 Scopus citations

Abstract

Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease.

Original language	English
Pages (from-to)	1899-1913
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	5
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01464
State	Published - Mar 10 2016

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Damalanka, V. C., Kim, Y., Alliston, K. R., Weerawarna, P. M., Galasiti Kankanamalage, A. C., Lushington, G. H., Mehzabeen, N., Battaile, K. P., Lovell, S., Chang, K. O., & Groutas, W. C. (2016). Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease. Journal of Medicinal Chemistry, 59(5), 1899-1913. https://doi.org/10.1021/acs.jmedchem.5b01464

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title = "Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease",

abstract = "Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease.",

author = "Damalanka, {Vishnu C.} and Yunjeong Kim and Alliston, {Kevin R.} and Weerawarna, {Pathum M.} and {Galasiti Kankanamalage}, {Anushka C.} and Lushington, {Gerald H.} and Nurjahan Mehzabeen and Battaile, {Kevin P.} and Scott Lovell and Chang, {Kyeong Ok} and Groutas, {William C.}",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = mar,

day = "10",

doi = "10.1021/acs.jmedchem.5b01464",

language = "English",

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Damalanka, VC, Kim, Y, Alliston, KR, Weerawarna, PM, Galasiti Kankanamalage, AC, Lushington, GH, Mehzabeen, N, Battaile, KP, Lovell, S, Chang, KO & Groutas, WC 2016, 'Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease', Journal of Medicinal Chemistry, vol. 59, no. 5, pp. 1899-1913. https://doi.org/10.1021/acs.jmedchem.5b01464

TY - JOUR

T1 - Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease

AU - Damalanka, Vishnu C.

AU - Kim, Yunjeong

AU - Alliston, Kevin R.

AU - Weerawarna, Pathum M.

AU - Galasiti Kankanamalage, Anushka C.

AU - Lushington, Gerald H.

AU - Mehzabeen, Nurjahan

AU - Battaile, Kevin P.

AU - Lovell, Scott

AU - Chang, Kyeong Ok

AU - Groutas, William C.

PY - 2016/3/10

Y1 - 2016/3/10

N2 - Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease.

AB - Human noroviruses are the primary causative agents of acute gastroenteritis and a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. Norovirus 3CL protease plays a vital role in viral replication by generating structural and nonstructural proteins via the cleavage of the viral polyprotein. Thus, molecules that inhibit the viral protease may have potential therapeutic value. We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based, permeable macrocyclic inhibitors of norovirus 3CL protease.

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U2 - 10.1021/acs.jmedchem.5b01464

DO - 10.1021/acs.jmedchem.5b01464

M3 - Article

C2 - 26823007

AN - SCOPUS:84960859366

SN - 0022-2623

VL - 59

SP - 1899

EP - 1913

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease

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