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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]
+ Show Author Affiliations
  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 Laboratory (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.
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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
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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.
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@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 = {Thu Apr 09 00:00:00 EDT 2015},
month = {Thu Apr 09 00:00:00 EDT 2015}
}
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https://doi.org/10.1021/jm5019934
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Works referenced in this record:

Progress towards the prevention and treatment of norovirus infections
journal, November 2013

  • Arias, Armando; Emmott, Edward; Vashist, Surender
  • Future Microbiology, Vol. 8, Issue 11
  • DOI: 10.2217/fmb.13.109

Norovirus in healthcare settings
journal, January 2014

Norovirus Gastroenteritis in Immunocompromised Patients
journal, November 2012

  • Bok, Karin; Green, Kim Y.
  • New England Journal of Medicine, Vol. 367, Issue 22
  • DOI: 10.1056/NEJMra1207742

Gastroenteritis in US Marines during Operation Iraqi Freedom
journal, February 2005

  • Thornton, S. A.; Sherman, S. S.; Farkas, T.
  • Clinical Infectious Diseases, Vol. 40, Issue 4
  • DOI: 10.1086/427501

Efficacy of Commonly Used Disinfectants for Inactivation of Human Noroviruses and Their Surrogates
journal, July 2013

Infection control for norovirus
journal, August 2014

  • Barclay, L.; Park, G. W.; Vega, E.
  • Clinical Microbiology and Infection, Vol. 20, Issue 8
  • DOI: 10.1111/1469-0691.12674

Norovirus: Targets and tools in antiviral drug discovery
journal, September 2014

  • Rocha-Pereira, Joana; Neyts, Johan; Jochmans, Dirk
  • Biochemical Pharmacology, Vol. 91, Issue 1
  • DOI: 10.1016/j.bcp.2014.05.021

Treatment of norovirus infections: Moving antivirals from the bench to the bedside
journal, May 2014

Epidemiology of human noroviruses and updates on vaccine development
journal, January 2014

  • Ramani, Sasirekha; Atmar, Robert L.; Estes, Mary K.
  • Current Opinion in Gastroenterology, Vol. 30, Issue 1
  • DOI: 10.1097/MOG.0000000000000022

Processing of Norwalk virus nonstructural proteins by a 3C-like cysteine proteinase
journal, April 2003

Norovirus gene expression and replication
journal, November 2013

  • Thorne, L. G.; Goodfellow, I. G.
  • Journal of General Virology, Vol. 95, Issue Pt_2
  • DOI: 10.1099/vir.0.059634-0

Design, synthesis, and evaluation of inhibitors of Norwalk virus 3C protease
journal, September 2011

  • Tiew, Kok-Chuan; He, Guijia; Aravapalli, Sridhar
  • Bioorganic & Medicinal Chemistry Letters, Vol. 21, Issue 18
  • DOI: 10.1016/j.bmcl.2011.07.016

Potent inhibition of norovirus 3CL protease by peptidyl α-ketoamides and α-ketoheterocycles
journal, July 2012

  • Mandadapu, Sivakoteswara Rao; Weerawarna, Pathum M.; Gunnam, Mallikarjuna Reddy
  • Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 14
  • DOI: 10.1016/j.bmcl.2012.05.055

Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors
journal, January 2013

  • Mandadapu, Sivakoteswara Rao; Gunnam, Mallikarjuna Reddy; Tiew, Kok-Chuan
  • Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 1
  • DOI: 10.1016/j.bmcl.2012.11.026

Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors
journal, December 2013

  • Prior, Allan M.; Kim, Yunjeong; Weerasekara, Sahani
  • Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 23
  • DOI: 10.1016/j.bmcl.2013.09.070

Potent inhibition of norovirus by dipeptidyl α-hydroxyphosphonate transition state mimics
journal, November 2013

  • Mandadapu, Sivakoteswara Rao; Gunnam, Mallikarjuna Reddy; Galasiti Kankanamalage, Anushka C.
  • Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 21
  • DOI: 10.1016/j.bmcl.2013.08.073

Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus
journal, July 2013

  • Mandadapu, Sivakoteswara Rao; Weerawarna, Pathum M.; Prior, Allan M.
  • Bioorganic & Medicinal Chemistry Letters, Vol. 23, Issue 13
  • DOI: 10.1016/j.bmcl.2013.05.021

Structural and inhibitor studies of norovirus 3C-like proteases
journal, December 2013

Synthesis, activity and structure–activity relationship of noroviral protease inhibitors
journal, January 2013

  • Deng, Lisheng; Muhaxhiri, Zana; Estes, Mary K.
  • MedChemComm, Vol. 4, Issue 10
  • DOI: 10.1039/c3md00219e

A Structural Study of Norovirus 3C Protease Specificity: Binding of a Designed Active Site-Directed Peptide Inhibitor
journal, January 2011

  • Hussey, Robert J.; Coates, Leighton; Gill, Raj S.
  • Biochemistry, Vol. 50, Issue 2
  • DOI: 10.1021/bi1008497

On the size of the active site in proteases. I. Papain
journal, April 1967

  • Schechter, Israel; Berger, Arieh
  • Biochemical and Biophysical Research Communications, Vol. 27, Issue 2, p. 157-162
  • DOI: 10.1016/S0006-291X(67)80055-X

Potent inhibition of Norwalk virus by cyclic sulfamide derivatives
journal, October 2011

  • Dou, Dengfeng; Tiew, Kok-Chuan; He, Guijia
  • Bioorganic & Medicinal Chemistry, Vol. 19, Issue 20
  • DOI: 10.1016/j.bmc.2011.08.054

Cyclosulfamide-based derivatives as inhibitors of noroviruses
journal, January 2012

  • Dou, Dengfeng; Mandadapu, Sivakoteswara R.; Alliston, Kevin R.
  • European Journal of Medicinal Chemistry, Vol. 47
  • DOI: 10.1016/j.ejmech.2011.10.019

Potent norovirus inhibitors based on the acyclic sulfamide scaffold
journal, March 2012

  • Dou, Dengfeng; Tiew, Kok-Chuan; Mandadapu, Sivakoteswara Rao
  • Bioorganic & Medicinal Chemistry, Vol. 20, Issue 6
  • DOI: 10.1016/j.bmc.2012.01.030

Design and synthesis of inhibitors of noroviruses by scaffold hopping
journal, October 2011

  • Dou, Dengfeng; Mandadapu, Sivakoteswara Rao; Alliston, Kevin R.
  • Bioorganic & Medicinal Chemistry, Vol. 19, Issue 19
  • DOI: 10.1016/j.bmc.2011.08.032

Inhibition of noroviruses by piperazine derivatives
journal, January 2012

  • Dou, Dengfeng; He, Guijia; Mandadapu, Sivakoteswara Rao
  • Bioorganic & Medicinal Chemistry Letters, Vol. 22, Issue 1
  • DOI: 10.1016/j.bmcl.2011.10.122

Halogen bonding for rational drug design and new drug discovery
journal, March 2012

Halogen bonding (X-bonding): A biological perspective: Halogen Bonding (X-Bonding)
journal, December 2012

  • Scholfield, Matthew R.; Zanden, Crystal M. Vander; Carter, Megan
  • Protein Science, Vol. 22, Issue 2
  • DOI: 10.1002/pro.2201

Specific Noncovalent Interactions at Protein-Ligand Interface: Implications for Rational Drug Design
journal, January 2012

.alpha.-Hydroxy Phosphinyl-Based Inhibitors of Human Renin
journal, October 1995

  • Patel, Dinesh V.; Rielly-Gauvin, Katherine; Ryono, Denis E.
  • Journal of Medicinal Chemistry, Vol. 38, Issue 22
  • DOI: 10.1021/jm00022a022

A Novel, Nonaqueous Method for Regeneration of Aldehydes from Bisulfite Adducts
journal, July 1999

  • Kjell, Douglas P.; Slattery, Brian J.; Semo, Michael J.
  • The Journal of Organic Chemistry, Vol. 64, Issue 15
  • DOI: 10.1021/jo990543v

Understanding Binding Selectivity toward Trypsin and Factor Xa: the Role of Aromatic Interactions
journal, March 2007

Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin
journal, August 2011

  • Sidhu, Preetpal Singh; Liang, Aiye; Mehta, Akul Y.
  • Journal of Medicinal Chemistry, Vol. 54, Issue 15
  • DOI: 10.1021/jm2005767

Cathepsin B, L, and S Cleave and Inactivate Secretory Leucoprotease Inhibitor
journal, September 2001

  • Taggart, Clifford C.; Lowe, Gregory J.; Greene, Catherine M.
  • Journal of Biological Chemistry, Vol. 276, Issue 36
  • DOI: 10.1074/jbc.M103220200

Structure-Based Design of a General Class of Mechanism-Based Inhibitors of the Serine Proteinases Employing a Novel Amino Acid-Derived Heterocyclic Scaffold †
journal, April 1997

  • Groutas, William C.; Kuang, Rongze; Venkataraman, Radhika
  • Biochemistry, Vol. 36, Issue 16
  • DOI: 10.1021/bi9628937

Conscripting the Active-Site Zinc Ion in Carboxypeptidase A in Inactivation Chemistry by a New Type of Irreversible Enzyme Inactivator
journal, August 1994

  • Tanaka, Yasuhiro; Grapsas, Ioannis; Dakoji, Srikanth
  • Journal of the American Chemical Society, Vol. 116, Issue 17
  • DOI: 10.1021/ja00096a001

Automatic indexing of rotation diffraction patterns
journal, February 1988

An introduction to data reduction: space-group determination, scaling and intensity statistics
journal, March 2011

  • Evans, Philip R.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
  • DOI: 10.1107/S090744491003982X

Solvent content of protein crystals
journal, April 1968

Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Developments in the CCP 4 molecular-graphics project
journal, November 2004

  • Potterton, Liz; McNicholas, Stuart; Krissinel, Eugene
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
  • DOI: 10.1107/S0907444904023716

Replication of Norovirus in Cell Culture Reveals a Tropism for Dendritic Cells and Macrophages
journal, November 2004

Antiviral Activity of a Small Molecule Deubiquitinase Inhibitor Occurs via Induction of the Unfolded Protein Response
journal, July 2012

Improved R-factors for diffraction data analysis in macromolecular crystallography
journal, April 1997

  • Diederichs, Kay; Karplus, P. Andrew
  • Nature Structural Biology, Vol. 4, Issue 4
  • DOI: 10.1038/nsb0497-269

Global indicators of X-ray data quality
journal, April 2001

Linking Crystallographic Model and Data Quality
journal, May 2012

Resolving Some Old Problems in Protein Crystallography
journal, May 2012

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    Works referencing / citing this record:

    Norovirus vaccines and potential antinorovirus drugs: recent advances and future perspectives
    journal, July 2015

    • Kocher, Jacob; Yuan, Lijuan
    • Future Virology, Vol. 10, Issue 7
    • DOI: 10.2217/fvl.15.57

    Inhibition of EV71 by curcumin in intestinal epithelial cells
    journal, January 2018

    Norovirus antivirals: Where are we now?
    journal, December 2018

    • Netzler, Natalie E.; Enosi Tuipulotu, Daniel; White, Peter A.
    • Medicinal Research Reviews, Vol. 39, Issue 3
    • DOI: 10.1002/med.21545

    Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease
    journal, April 2019

    • Galasiti Kankanamalage, Anushka C.; Weerawarna, Pathum M.; Rathnayake, Athri D.
    • Proteins: Structure, Function, and Bioinformatics, Vol. 87, Issue 7
    • DOI: 10.1002/prot.25682

    Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors
    journal, February 2019

    • Chang, Kyeong-Ok; Kim, Yunjeong; Lovell, Scott
    • Viruses, Vol. 11, Issue 2
    • DOI: 10.3390/v11020197

    Protease inhibitors broadly effective against feline, ferret and mink coronaviruses
    journal, December 2018

    Structure-based design and synthesis of triazole-based macrocyclic inhibitors of norovirus protease: Structural, biochemical, spectroscopic, and antiviral studies
    journal, August 2016

    • Weerawarna, Pathum M.; Kim, Yunjeong; Galasiti Kankanamalage, Anushka C.
    • European Journal of Medicinal Chemistry, Vol. 119
    • DOI: 10.1016/j.ejmech.2016.04.013

    Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element
    journal, April 2018

    • Galasiti Kankanamalage, Anushka C.; Kim, Yunjeong; Damalanka, Vishnu C.
    • European Journal of Medicinal Chemistry, Vol. 150
    • DOI: 10.1016/j.ejmech.2018.03.004

    Inhibition of EV71 by curcumin in intestinal epithelial cells
    journal, January 2018

    Therapeutics and Immunoprophylaxis Against Noroviruses and Rotaviruses: The Past, Present, and Future
    journal, May 2018

    Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors
    journal, February 2019

    • Chang, Kyeong-Ok; Kim, Yunjeong; Lovell, Scott
    • Viruses, Vol. 11, Issue 2
    • DOI: 10.3390/v11020197
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