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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. Herein we describe 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.

Authors:
 [1];  [2];  [1];  [1];  [1];  [3];  [4];  [5];  [4];  [2];  [1]
  1. Wichita State Univ., Wichita, KS (United States)
  2. Kansas State Univ., Manhattan, KS (United States). College of Veterinary Medicine
  3. LiS Consulting, Lawrence, KS (United States)
  4. Univ. of Kansas, Lawrence, KS (United States)
  5. Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS), IMCA-CAT; Hauptman-Woodward Medical Research Inst., Argonne, IL (United States)
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); National Institutes of Health (NIH); National Center for Research Resources; National Institute of General Medical Sciences (NIGMS); Industrial Macromolecular Crystallography Association
OSTI Identifier:
1248389
Grant/Contract Number:  
R01 AI109039; 5P20RR017708-10; 8P20GM103420-10; AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 59; Journal Issue: 5; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Peptides and proteins; Inhibitors; Noncovalent interactions; Permeability; Macrocycles

Citation Formats

Damalanka, Vishnu C., Kim, Yunjeong, Alliston, Kevin R., Weerawarna, Pathum M., Galasiti Kankanamalage, Anushka C., Lushington, Gerald H., Mehzabeen, Nurjahan, Battaile, Kevin P., Lovell, Scott, Chang, Kyeong-Ok, and Groutas, William C. Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.5b01464.
Damalanka, Vishnu C., Kim, Yunjeong, Alliston, Kevin R., Weerawarna, Pathum M., Galasiti Kankanamalage, Anushka C., Lushington, Gerald H., Mehzabeen, Nurjahan, Battaile, Kevin P., Lovell, Scott, Chang, Kyeong-Ok, & Groutas, William C. Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease. United States. https://doi.org/10.1021/acs.jmedchem.5b01464
Damalanka, Vishnu C., Kim, Yunjeong, Alliston, Kevin R., Weerawarna, Pathum M., Galasiti Kankanamalage, Anushka C., Lushington, Gerald H., Mehzabeen, Nurjahan, Battaile, Kevin P., Lovell, Scott, Chang, Kyeong-Ok, and Groutas, William C. Mon . "Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease". United States. https://doi.org/10.1021/acs.jmedchem.5b01464. https://www.osti.gov/servlets/purl/1248389.
@article{osti_1248389,
title = {Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease},
author = {Damalanka, Vishnu C. and Kim, Yunjeong and Alliston, Kevin R. and Weerawarna, Pathum M. and Galasiti Kankanamalage, Anushka C. and Lushington, Gerald H. and Mehzabeen, Nurjahan and Battaile, Kevin P. and Lovell, Scott and Chang, Kyeong-Ok and Groutas, William C.},
abstractNote = {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. Herein we describe 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.},
doi = {10.1021/acs.jmedchem.5b01464},
url = {https://www.osti.gov/biblio/1248389}, journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 5,
volume = 59,
place = {United States},
year = {2016},
month = {2}
}

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Works referencing / citing this record:

Oxadiazole grafts in peptide macrocycles
journal, October 2016