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Title: Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies

Abstract

Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [3];  [4];  [3];  [2];  [1]
  1. Wichita State Univ., Wichita, KS (United States). Dept. of Chemistry
  2. Kansas State Univ., Manhattan, KS (United States). Dept. of Diagnostic Medicine & Pathobiology
  3. Univ. of Kansas, Lawrence, KS (United States). Protein Structure Lab.
  4. Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS). Hauptman-Woodward Medical Research Inst.
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1179476
Grant/Contract Number:  
AC02-06CH11357; AI109039; 5P20RR017708-10; 8P20GM103420-10
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 7; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE

Citation Formats

Galasiti Kankanamalage, Anushka C., Kim, Yunjeong, Weerawarna, Pathum M., Uy, Roxanne Adeline Z., Damalanka, Vishnu C., Mandadapu, Sivakoteswara Rao, Alliston, Kevin R., Mehzabeen, Nurjahan, Battaile, Kevin P., Lovell, Scott, Chang, Kyeong-Ok, and Groutas, William C. Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies. United States: N. p., 2015. Web. doi:10.1021/jm5019934.
Galasiti Kankanamalage, Anushka C., Kim, Yunjeong, Weerawarna, Pathum M., Uy, Roxanne Adeline Z., Damalanka, Vishnu C., Mandadapu, Sivakoteswara Rao, Alliston, Kevin R., Mehzabeen, Nurjahan, Battaile, Kevin P., Lovell, Scott, Chang, Kyeong-Ok, & Groutas, William C. Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies. United States. https://doi.org/10.1021/jm5019934
Galasiti Kankanamalage, Anushka C., Kim, Yunjeong, Weerawarna, Pathum M., Uy, Roxanne Adeline Z., Damalanka, Vishnu C., Mandadapu, Sivakoteswara Rao, Alliston, Kevin R., Mehzabeen, Nurjahan, Battaile, Kevin P., Lovell, Scott, Chang, Kyeong-Ok, and Groutas, William C. Thu . "Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies". United States. https://doi.org/10.1021/jm5019934. https://www.osti.gov/servlets/purl/1179476.
@article{osti_1179476,
title = {Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies},
author = {Galasiti Kankanamalage, Anushka C. and Kim, Yunjeong and Weerawarna, Pathum M. and Uy, Roxanne Adeline Z. and Damalanka, Vishnu C. and Mandadapu, Sivakoteswara Rao and Alliston, Kevin R. and Mehzabeen, Nurjahan and Battaile, Kevin P. and Lovell, Scott and Chang, Kyeong-Ok and Groutas, William C.},
abstractNote = {Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.},
doi = {10.1021/jm5019934},
journal = {Journal of Medicinal Chemistry},
number = 7,
volume = 58,
place = {United States},
year = {2015},
month = {4}
}

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