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.
authors.affiliation: Department of Chemistry, Wichita State University , Wichita, Kansas 67260, United States.
authors.forename: Vishnu C
authors.initials: VC
authors.lastname: Damalanka
authors.affiliation: Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University , Manhattan, Kansas 66506, United States.
authors.forename: Yunjeong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Wichita State University , Wichita, Kansas 67260, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Alliston
authors.affiliation: Department of Chemistry, Wichita State University , Wichita, Kansas 67260, United States.
authors.forename: Pathum M
authors.initials: PM
authors.lastname: Weerawarna
authors.affiliation: Department of Chemistry, Wichita State University , Wichita, Kansas 67260, United States.
authors.forename: Anushka C
authors.initials: AC
authors.lastname: Galasiti Kankanamalage
authors.affiliation: LiS Consulting , Lawrence, Kansas 66046, United States.
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Lushington
authors.affiliation: Protein Structure Laboratory, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Nurjahan
authors.initials: N
authors.lastname: Mehzabeen
authors.affiliation: IMCA-CAT, Hauptman-Woodward Medical Research Institute, APS Argonne National Laboratory, Argonne, Illinois 60439, United States.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Battaile
authors.affiliation: Protein Structure Laboratory, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Lovell
authors.affiliation: Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University , Manhattan, Kansas 66506, United States.
authors.forename: Kyeong-Ok
authors.initials: KO
authors.lastname: Chang
authors.affiliation: Department of Chemistry, Wichita State University , Wichita, Kansas 67260, United States.
authors.forename: William C
authors.initials: WC
authors.lastname: Groutas
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D029322:Norovirus / Q000187:drug effects* / Q000201:enzymology*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D047028:Macrocyclic Compounds; D010069:Oxadiazoles; D011480:Protease Inhibitors; D010447:Peptide Hydrolases
references.citation: Biochem Biophys Res Commun. 1967 Apr 20;27(2):157-62
references.pmid: 6035483
references.citation: Bioorg Med Chem Lett. 2011 Sep 15;21(18):5315-9
references.pmid: 21802286
references.citation: Future Microbiol. 2015;10(1):53-67
references.pmid: 25598337
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references.pmid: 20383002
references.citation: J Med Chem. 2015 Apr 9;58(7):3144-55
references.pmid: 25761614
references.citation: Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):72-82
references.pmid: 16369096
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):12-21
references.pmid: 20057044
references.citation: Future Med Chem. 2012 Jul;4(11):1409-38
references.pmid: 22857532
references.citation: J Virol. 2012 Nov;86(21):11754-62
references.pmid: 22915796
references.citation: J Infect Dis. 2012 Jun;205(11):1622-4
references.pmid: 22573872
references.citation: Science. 2012 May 25;336(6084):986-7
references.pmid: 22628641
references.citation: N Engl J Med. 2012 Nov 29;367(22):2126-32
references.pmid: 23190223
references.citation: Bioorg Med Chem Lett. 2013 Nov 1;23(21):5941-4
references.pmid: 24054123
references.citation: Bioorg Med Chem Lett. 2013 Jul 1;23(13):3709-12
references.pmid: 23727045
references.citation: Chem Rev. 2010 Jun 9;110(6):PR1-31
references.pmid: 20377171
references.citation: J Gen Virol. 2014 Feb;95(Pt 2):278-91
references.pmid: 24243731
references.citation: J Med Chem. 2014 Jan 23;57(2):278-95
references.pmid: 24044773
references.citation: Virology. 2012 Feb 20;423(2):125-33
references.pmid: 22200497
references.citation: Virus Res. 2002 Oct;89(1):29-39
references.pmid: 12367748
references.citation: Science. 2012 May 25;336(6084):1030-3
references.pmid: 22628654
references.citation: Biochemistry. 2011 Jan 18;50(2):240-9
references.pmid: 21128685
references.citation: J Med Chem. 2011 Apr 14;54(7):1961-2004
references.pmid: 21381769
references.citation: Bioorg Med Chem Lett. 2012 Jul 15;22(14):4820-6
references.pmid: 22698498
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):282-92
references.pmid: 21460446
references.citation: Biochem J. 2014 Dec 15;464(3):461-72
references.pmid: 25275273
references.citation: Protein Sci. 2013 Mar;22(3):347-57
references.pmid: 23319456
references.citation: Chem Biol Drug Des. 2013 Jan;81(1):136-47
references.pmid: 23253135
references.citation: J Am Chem Soc. 2006 Mar 1;128(8):2510-1
references.pmid: 16492015
references.citation: Lancet Infect Dis. 2014 Aug;14(8):725-30
references.pmid: 24981041
references.citation: J Virol. 2013 Apr;87(8):4281-92
references.pmid: 23365454
references.citation: J Mol Biochem. 2012;1(2):76-85
references.pmid: 27882309
references.citation: Nat Rev Drug Discov. 2014 Feb;13(2):85-9
references.pmid: 24481294
references.citation: Emerg Infect Dis. 2013 Aug;19(8):1198-205
references.pmid: 23876403
references.citation: Curr Med Chem. 2001 Jul;8(8):893-907
references.pmid: 11375757
references.citation: Nat Rev Drug Discov. 2010 Sep;9(9):690-701
references.pmid: 20811381
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
references.pmid: 20124702
references.citation: Chem Rev. 2005 Mar;105(3):973-99
references.pmid: 15755082
references.citation: Clin Microbiol Rev. 2015 Jan;28(1):134-64
references.pmid: 25567225
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2288-94
references.pmid: 15572783
references.citation: J Med Chem. 1998 May 21;41(11):1745-8
references.pmid: 9599225
references.citation: Nat Struct Biol. 1997 Apr;4(4):269-75
references.pmid: 9095194
references.citation: Virus Res. 2005 Jun;110(1-2):91-7
references.pmid: 15845259
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
references.pmid: 20124692
references.citation: J Pathol. 2015 Jan;235(2):206-16
references.pmid: 25312350
references.citation: Nat Protoc. 2015 Dec;10(12):1939-47
references.pmid: 26513671
references.citation: CMAJ. 2013 Nov 5;185(16):1381-2
references.pmid: 24003105
references.citation: Virology. 2003 Apr 10;308(2):216-24
references.pmid: 12706072
references.citation: Curr Drug Metab. 2009 Sep;10(7):661-91
references.pmid: 19702530
references.citation: Discov Med. 2010 Jul;10(50):61-70
references.pmid: 20670600