title: Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1.
abstract: Influenza is a continuing world-wide public health problem that causes significant morbidity and mortality during seasonal epidemics and sporadic pandemics. The existing vaccination program is variably effective from year to year, and drug resistance to available antivirals is a growing problem, making the development of additional antivirals an important challenge. Influenza virus non-structural protein 1 (NS1) is the centerpiece of the viral response to the host interferon (IFN) system. NS1 was demonstrated previously to be a potential therapeutic target for antiviral therapy by the identification of specific small-molecule inhibitors. One inhibitory compound, NSC125044, was subjected to chemical evaluation. Initial synthetic work comprised simplifying the core structure by removing unwanted functionality and determination of key features important for activity. Several subclasses of molecules were designed and synthesized to further probe activity and develop the basis for a structure-activity relationship. Apparent potency, as judged by activity in virus replication assays, increased dramatically for some analogs, without cytotoxicity. Results suggest that the target binding site tolerates hydrophobic bulk as well as having a preference for weakly basic substituents.
authors.affiliation: University of Virginia, Department of Chemistry, Charlottesville, VA 22904, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Jablonski
authors.forename: Dipwanita
authors.initials: D
authors.lastname: Basu
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Engel
authors.forename: H Mario
authors.initials: HM
authors.lastname: Geysen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001554:Benzene / Q000737:chemistry; D002460:Cell Line; D004285:Dogs; D015195:Drug Design; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009975:Orthomyxoviridae / Q000378:metabolism; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C571816:2-hydroxybenzohydrazide; D000998:Antiviral Agents; D006834:Hydrazines; C085820:INS1 protein, influenza virus; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; D001554:Benzene
references.citation: Cell Host Microbe. 2009 May 8;5(5):420-1
references.pmid: 19454344
references.citation: Science. 2006 Apr 21;312(5772):384-8
references.pmid: 16627734
references.citation: J Virol. 2007 Jul;81(13):7011-21
references.pmid: 17442719
references.citation: Virology. 2003 Mar 15;307(2):386-95
references.pmid: 12667806
references.citation: Microbes Infect. 2011 May;13(5):470-8
references.pmid: 21276873
references.citation: EMBO J. 1999 Apr 15;18(8):2273-83
references.pmid: 10205180
references.citation: Cell Host Microbe. 2009 May 8;5(5):439-49
references.pmid: 19454348
references.citation: J Gen Virol. 1992 Dec;73 ( Pt 12):3325-9
references.pmid: 1469370
references.citation: J Virol. 2007 Dec;81(23):12720-9
references.pmid: 17804500
references.citation: Angew Chem Int Ed Engl. 2006 Nov 13;45(44):7330-4
references.pmid: 17051628
references.citation: Microbes Infect. 2001 Jan;3(1):81-7
references.pmid: 11226857
references.citation: JAMA. 2003 Jan 8;289(2):179-86
references.pmid: 12517228
references.citation: Arch Intern Med. 2005 Feb 14;165(3):265-72
references.pmid: 15710788
references.citation: Mol Cell. 1998 Jun;1(7):991-1000
references.pmid: 9651582
references.citation: J Virol. 2007 Mar;81(5):2318-27
references.pmid: 17182679
references.citation: Virology. 2007 Jun 20;363(1):236-43
references.pmid: 17320139
references.citation: Nature. 2006 Jul 6;442(7098):37
references.pmid: 16823443
references.citation: Trends Pharmacol Sci. 2009 Jun;30(6):269-77
references.pmid: 19428126
references.citation: J Virol. 2009 Feb;83(4):1881-91
references.pmid: 19052087
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7100-5
references.pmid: 16627618
references.citation: Virology. 1998 Dec 20;252(2):324-30
references.pmid: 9878611
references.citation: Thorax. 2010 Oct;65(10):855-6
references.pmid: 20861289
references.citation: Virology. 2003 May 10;309(2):181-9
references.pmid: 12758165
references.citation: Vaccine. 2006 Sep 29;24(40-41):6367-70
references.pmid: 17240560
references.citation: N Engl J Med. 2008 Jan 17;358(3):261-73
references.pmid: 18199865
references.citation: Virology. 2008 Aug 15;378(1):1-5
references.pmid: 18585749
references.citation: J Infect Dis. 2006 Nov 1;194 Suppl 2:S111-8
references.pmid: 17163383
references.citation: J Biol Chem. 2007 Jul 13;282(28):20584-92
references.pmid: 17475623
references.citation: JAMA. 2004 Sep 15;292(11):1333-40
references.pmid: 15367555
references.citation: Am J Respir Cell Mol Biol. 2007 Mar;36(3):263-9
references.pmid: 17053203
references.citation: J Gen Virol. 2011 Jan;92(Pt 1):60-70
references.pmid: 20881091
references.citation: Eur J Pediatr. 2011 Mar;170(3):371-8
references.pmid: 21274563
references.citation: N Engl J Med. 2006 Nov 23;355(21):2174-7
references.pmid: 17124014
references.citation: Pharmacol Ther. 1998 Apr;78(1):29-46
references.pmid: 9593328