title: An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model.
abstract: Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.
authors.affiliation: Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Krumm
authors.forename: Dan
authors.initials: D
authors.lastname: Yan
authors.forename: Elise S
authors.initials: ES
authors.lastname: Hovingh
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Evers
authors.forename: Theresa
authors.initials: T
authors.lastname: Enkirch
authors.forename: G Prabhakar
authors.initials: GP
authors.lastname: Reddy
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.forename: Manohar T
authors.initials: MT
authors.lastname: Saindane
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.forename: George
authors.initials: G
authors.lastname: Painter
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
authors.forename: Veronika
authors.initials: V
authors.lastname: von Messling
authors.forename: Richard K
authors.initials: RK
authors.lastname: Plemper
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002522:Chlorocebus aethiops; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004217:Distemper Virus, Canine / Q000187:drug effects / Q000201:enzymology; D024882:Drug Resistance, Viral / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005289:Ferrets / Q000821:virology; D008297:Male; D018185:Morbillivirus Infections / Q000188:drug therapy* / Q000821:virology; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014709:Vero Cells
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D012321:DNA-Directed RNA Polymerases
references.citation: Lancet. 2012 Jun 9;379(9832):2130-1
references.pmid: 22534000
references.citation: Virology. 2012 Dec 5;434(1):129-36
references.pmid: 23062737
references.citation: Curr Opin Virol. 2012 Jun;2(3):248-55
references.pmid: 22483507
references.citation: Philos Trans R Soc Lond B Biol Sci. 2013 Jun 24;368(1623):20120148
references.pmid: 23798696
references.citation: J Infect Dis. 2004 May 1;189 Suppl 1:S4-16
references.pmid: 15106083
references.citation: Lancet. 2012 Jun 9;379(9832):2173-8
references.pmid: 22534001
references.citation: Science. 1997 Jan 3;275(5296):65-7
references.pmid: 8974392
references.citation: Nat Rev Microbiol. 2006 Dec;4(12):900-8
references.pmid: 17088933
references.citation: Antimicrob Agents Chemother. 2009 Sep;53(9):3860-70
references.pmid: 19528268
references.citation: J Infect Dis. 1999 Oct;180(4):950-8
references.pmid: 10479117
references.citation: Vaccine. 2012 Feb 27;30(10):1855-64
references.pmid: 22230590
references.citation: Virology. 2007 Jun 5;362(2):404-10
references.pmid: 17289104
references.citation: Immunol Rev. 2010 Jul;236:176-89
references.pmid: 20636817
references.citation: Anal Biochem. 2000 Oct 15;285(2):194-204
references.pmid: 11017702
references.citation: Chem Biodivers. 2004 Jan;1(1):44-64
references.pmid: 17191775
references.citation: PLoS One. 2011;6(5):e20069
references.pmid: 21603574
references.citation: Lancet. 2012 Jan 14;379(9811):153-64
references.pmid: 21855993
references.citation: Nat Med. 2003 Sep;9(9):1209-13
references.pmid: 12925847
references.citation: Lancet. 2004 Mar 6;363(9411):750
references.pmid: 15016483
references.citation: J Virol. 2012 Jul;86(14):7508-19
references.pmid: 22553334
references.citation: Curr Top Microbiol Immunol. 2009;330:73-87
references.pmid: 19203105
references.citation: Vaccine. 2012 Jul 6;30(32):4709-16
references.pmid: 22549089
references.citation: J Virol. 2003 Sep;77(18):9943-50
references.pmid: 12941904
references.citation: Vaccine. 2000 Oct 15;19(4-5):523-9
references.pmid: 11027817
references.citation: Am J Vet Res. 1956 Jan;17(62):103-8
references.pmid: 13283234
references.citation: Lancet. 2011 Aug 6;378(9790):526-35
references.pmid: 21664679
references.citation: Antimicrob Agents Chemother. 2007 Jul;51(7):2293-303
references.pmid: 17470652
references.citation: PLoS Pathog. 2011 Jan 27;7(1):e1001263
references.pmid: 21304593
references.citation: J Med Chem. 2012 May 10;55(9):4220-30
references.pmid: 22480182
references.citation: Microbiol Mol Biol Rev. 2012 Mar;76(1):16-32
references.pmid: 22390970
references.citation: PLoS Pathog. 2012;8(8):e1002885
references.pmid: 22952446
references.citation: Virol J. 2013 Sep 12;10:283
references.pmid: 24025157
references.citation: JAMA. 1962 Mar 17;179:848-53
references.pmid: 13876943
references.citation: Virus Res. 2004 Feb;99(2):139-45
references.pmid: 14749179
references.citation: Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2013 Sep;56(9):1238-42
references.pmid: 23990085
references.citation: Public Health Rep. 2011 Jul-Aug;126 Suppl 2:135-46
references.pmid: 21812176
references.citation: Lancet. 2004 Feb 14;363(9408):569-70
references.pmid: 14975626
references.citation: J Virol. 2014 Mar;88(5):2941-50
references.pmid: 24371065
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14216-21
references.pmid: 15377791
references.citation: MMWR Morb Mortal Wkly Rep. 2012 Apr 20;61:253-7
references.pmid: 22513526
references.citation: J Virol. 2003 Dec;77(23):12579-91
references.pmid: 14610181