title: Mucosal delivery of a double-stapled RSV peptide prevents nasopulmonary infection.
abstract: Respiratory syncytial virus (RSV) infection accounts for approximately 64 million cases of respiratory disease and 200,000 deaths worldwide each year, yet no broadly effective prophylactic or treatment regimen is available. RSV deploys paired, self-associating, heptad repeat domains of its fusion protein, RSV-F, to form a fusogenic 6-helix bundle that enables the virus to penetrate the host cell membrane. Here, we developed hydrocarbon double-stapled RSV fusion peptides that exhibit stabilized α-helical structure and striking proteolytic resistance. Pretreatment with double-stapled RSV peptides that specifically bound to the RSV fusion bundle inhibited infection by both laboratory and clinical RSV isolates in cells and murine infection models. Intranasal delivery of a lead double-stapled RSV peptide effectively prevented viral infection of the nares. A chitosan-based nanoparticle preparation markedly enhanced pulmonary delivery, further preventing progression of RSV infection to the lung. Thus, our results provide a strategy for inhibiting RSV infection by mucosal and endotracheal delivery of double-stapled RSV fusion peptides.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Bird
authors.forename: Sandhya
authors.initials: S
authors.lastname: Boyapalle
authors.forename: Terianne
authors.initials: T
authors.lastname: Wong
authors.forename: Kwadwo
authors.initials: K
authors.lastname: Opoku-Nsiah
authors.forename: Raminder
authors.initials: R
authors.lastname: Bedi
authors.forename: W Christian
authors.initials: WC
authors.lastname: Crannell
authors.forename: Alisa F
authors.initials: AF
authors.lastname: Perry
authors.forename: Huy
authors.initials: H
authors.lastname: Nguyen
authors.forename: Viviana
authors.initials: V
authors.lastname: Sampayo
authors.forename: Ankita
authors.initials: A
authors.lastname: Devareddy
authors.forename: Subhra
authors.initials: S
authors.lastname: Mohapatra
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Mohapatra
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
mesh_terms: D000818:Animals; D002460:Cell Line; D048271:Chitosan / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry; D009668:Nose Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011024:Pneumonia, Viral / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012136:Respiratory Syncytial Viruses; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010455:Peptides; D014760:Viral Fusion Proteins; D048271:Chitosan
references.citation: Science. 2001 Feb 2;291(5505):884-8
references.pmid: 11229405
references.citation: Nat Med. 2005 Jan;11(1):56-62
references.pmid: 15619625
references.citation: J Virol. 2003 May;77(9):5054-64
references.pmid: 12692208
references.citation: PLoS One. 2013 Aug 14;8(8):e72217
references.pmid: 23967287
references.citation: MMWR Morb Mortal Wkly Rep. 2000 Dec 8;49(48):1091-3
references.pmid: 11130859
references.citation: Nat Med. 2005 Jan;11(1):50-5
references.pmid: 15619632
references.citation: Retrovirology. 2008 Dec 10;5:111
references.pmid: 19077194
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):308-13
references.pmid: 19966279
references.citation: Antivir Chem Chemother. 1999 May;10(3):135-9
references.pmid: 10431613
references.citation: Curr Protoc Chem Biol. 2011 Sep 1;3(3):99-117
references.pmid: 23801563
references.citation: J Infect Dis. 1999 Jan;179(1):25-30
references.pmid: 9841818
references.citation: Methods Enzymol. 2008;446:369-86
references.pmid: 18603134
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2186-91
references.pmid: 8700906
references.citation: J Virol. 2009 May;83(9):4185-94
references.pmid: 19211758
references.citation: J Am Chem Soc. 2006 Oct 11;128(40):13284-9
references.pmid: 17017810
references.citation: Nat Med. 2000 Jan;6(1):35-40
references.pmid: 10613821
references.citation: J Virol. 2012 Feb;86(3):1832-43
references.pmid: 22090136
references.citation: Vaccine. 2007 Jan 15;25(5):846-55
references.pmid: 17074423
references.citation: Clin Microbiol Rev. 2000 Jul;13(3):371-84
references.pmid: 10885982
references.citation: Biochemistry. 2000 Sep 26;39(38):11684-95
references.pmid: 10995236
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14093-8
references.pmid: 20660316
references.citation: J Virol. 2004 Dec;78(24):13717-26
references.pmid: 15564481
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14172-7
references.pmid: 11106388
references.citation: J Virol. 2006 Feb;80(4):2013-8
references.pmid: 16439557
references.citation: Hum Gene Ther. 2002 Aug 10;13(12):1415-25
references.pmid: 12215263
references.citation: Eur Respir J. 2011 Aug;38(2):401-8
references.pmid: 21148224
references.citation: Evid Based Complement Alternat Med. 2013;2013:698206
references.pmid: 24250719
references.citation: Vaccine. 1999 Oct 14;18(5-6):558-67
references.pmid: 10519947
references.citation: Nat Med. 1998 Nov;4(11):1302-7
references.pmid: 9809555
references.citation: Science. 2013 May 31;340(6136):1113-7
references.pmid: 23618766
references.citation: J Clin Microbiol. 2005 May;43(5):2356-62
references.pmid: 15872266
references.citation: Science. 2004 Sep 3;305(5689):1466-70
references.pmid: 15353804
references.citation: Virology. 2000 Jun 5;271(2):264-75
references.pmid: 10860881
references.citation: J Gen Virol. 2014 Feb;95(Pt 2):301-306
references.pmid: 24136365
references.citation: Can J Physiol Pharmacol. 2005 Feb;83(2):198-213
references.pmid: 15791294
references.citation: J Antimicrob Chemother. 2005 Mar;55(3):289-92
references.pmid: 15681582
references.citation: PLoS One. 2012;7(2):e29386
references.pmid: 22383950
references.citation: Chem Biol. 2001 Jul;8(7):645-59
references.pmid: 11451666
references.citation: JAMA. 2003 Jan 8;289(2):179-86
references.pmid: 12517228
references.citation: N Engl J Med. 1986 Jul 10;315(2):77-81
references.pmid: 3724802
references.citation: Science. 2013 Nov 1;342(6158):592-8
references.pmid: 24179220
references.citation: Drugs Aging. 2005;22(7):577-87
references.pmid: 16038573