Dual Inhibition of Human Parainfluenza Type 3 and Respiratory Syncytial Virus Infectivity with a Single Agent

Outlaw, Victor K.; Bottom-Tanzer, Samantha; Kreitler, Dale F.; Gellman, Samuel H.; Porotto, Matteo; Moscona, Anne

doi:10.1021/jacs.9b04615

Dual Inhibition of Human Parainfluenza Type 3 and Respiratory Syncytial Virus Infectivity with a Single Agent

Journal Article · Wed Jul 03 00:00:00 EDT 2019 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.9b04615· OSTI ID:1562709

^[1]; Bottom-Tanzer, Samantha ^[2]; ^[1]; ^[1]; Porotto, Matteo ^[3]; Moscona, Anne ^[2]

Univ. of Wisconsin, Madison, WI (United States)
Columbia Univ. Medical Center, New York, NY (United States)
Columbia Univ. Medical Center, New York, NY (United States); Univ. of Campania (Italy)

Human parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) cause lower respiratory infection in infants and young children. There are no vaccines for these pathogens, and existing treatments have limited or questionable efficacy. Infection by HPIV3 or RSV requires fusion of the viral and cell membranes, a process mediated by a trimeric fusion glycoprotein (F) displayed on the viral envelope. Once triggered, the pre-fusion form of F undergoes a series of conformational changes that first extend the molecule to allow for insertion of the hydrophobic fusion peptide into the target cell membrane and then refold the trimeric assembly into an energetically stable post-fusion state, a process that drives the merger of the viral and host cell membranes. Peptides derived from defined regions of HPIV3 F inhibit infection by HPIV3 by interfering with the structural transitions of the trimeric F assembly. Here we describe lipopeptides derived from the C-terminal heptad repeat (HRC) domain of HPIV3 F that potently inhibit infection by both HPIV3 and RSV. The lead peptide inhibits RSV infection as effectively as does a peptide corresponding to the RSV HRC domain itself. We show that the inhibitors bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F with high affinity. Finally, co-crystal structures of inhibitors bound to the HRN domains of HPIV3 or RSV F reveal remarkably different modes of binding in the N-terminal segment of the inhibitor.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1562709

Journal Information:: Journal of the American Chemical Society, Journal Name: Journal of the American Chemical Society Journal Issue: 32 Vol. 141; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (34)

A synthetic peptide corresponding to a conserved heptad repeat domain is a potent inhibitor of Sendai virus-cell fusion: an emerging similarity with functional domains of other viruses. Rapaport, D.; Ovadia, M.; Shai, Y. The EMBO Journal, Vol. 14, Issue 22 https://doi.org/10.1002/j.1460-2075.1995.tb00239.x	journal	November 1995
Peptides Corresponding to the Heptad Repeat Sequence of Human Parainfluenza Virus Fusion Protein Are Potent Inhibitors of Virus Infection Yao, Qizhi; Compans, Richard W. Virology, Vol. 223, Issue 1 https://doi.org/10.1006/viro.1996.0459	journal	September 1996
Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis Nair, Harish; Nokes, D. James; Gessner, Bradford D. The Lancet, Vol. 375, Issue 9725 https://doi.org/10.1016/S0140-6736(10)60206-1	journal	May 2010
Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study Shi, Ting; McAllister, David A.; O'Brien, Katherine L. The Lancet, Vol. 390, Issue 10098 https://doi.org/10.1016/S0140-6736(17)30938-8	journal	September 2017
Lipophilicity is a key factor to increase the antiviral activity of HIV neutralizing antibodies Augusto, Marcelo T.; Hollmann, Axel; Troise, Fulvia Colloids and Surfaces B: Biointerfaces, Vol. 152 https://doi.org/10.1016/j.colsurfb.2017.01.032	journal	April 2017
The Cell Biology of Acute Childhood Respiratory Disease: Therapeutic Implications Loughlin, Gerald M.; Moscona, Anne Pediatric Clinics of North America, Vol. 53, Issue 5 https://doi.org/10.1016/j.pcl.2006.08.004	journal	October 2006
Capping and α-helix stability Serrano, Luis; Fersht, Alan R. Nature, Vol. 342, Issue 6247 https://doi.org/10.1038/342296a0	journal	November 1989
Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes Matthews, Tom; Salgo, Miklos; Greenberg, Michael Nature Reviews Drug Discovery, Vol. 3, Issue 3 https://doi.org/10.1038/nrd1331	journal	March 2004
Viral membrane fusion Harrison, Stephen C. Nature Structural & Molecular Biology, Vol. 15, Issue 7 https://doi.org/10.1038/nsmb.1456	journal	July 2008
A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol Quinn, Killian; Traboni, Cinzia; Penchala, Sujan Dily Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-09230-0	journal	August 2017
Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides Mathieu, Cyrille; Augusto, Marcelo T.; Niewiesk, Stefan Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/srep43610	journal	March 2017
Sulfono-γ-AA modified peptides that inhibit HIV-1 fusion Bolarinwa, Olapeju; Zhang, Meng; Mulry, Erin Organic & Biomolecular Chemistry, Vol. 16, Issue 42 https://doi.org/10.1039/C8OB02159G	journal	January 2018
Structure of the uncleaved ectodomain of the paramyxovirus (hPIV3) fusion protein Yin, H. -S.; Paterson, R. G.; Wen, X. Proceedings of the National Academy of Sciences, Vol. 102, Issue 26 https://doi.org/10.1073/pnas.0503989102	journal	June 2005
The entry of entry inhibitors: A fusion of science and medicine Moore, John P.; Doms, Robert W. Proceedings of the National Academy of Sciences, Vol. 100, Issue 19 https://doi.org/10.1073/pnas.1932511100	journal	September 2003
Structural characterization of the human respiratory syncytial virus fusion protein core Zhao, X.; Singh, M.; Malashkevich, V. N. Proceedings of the National Academy of Sciences, Vol. 97, Issue 26 https://doi.org/10.1073/pnas.260499197	journal	December 2000
Propensity for a leucine zipper-like domain of human immunodeficiency virus type 1 gp41 to form oligomers correlates with a role in virus-induced fusion rather than assembly of the glycoprotein complex. Wild, C.; Dubay, J. W.; Greenwell, T. Proceedings of the National Academy of Sciences, Vol. 91, Issue 26 https://doi.org/10.1073/pnas.91.26.12676	journal	December 1994
Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion. Lambert, D. M.; Barney, S.; Lambert, A. L. Proceedings of the National Academy of Sciences, Vol. 93, Issue 5 https://doi.org/10.1073/pnas.93.5.2186	journal	March 1996
The Effect of Respiratory Synctial Virus on Chemokine Release by Differentiated Airway Epithelium Mellow, Thomas E.; Murphy, Paula C.; Carson, Johnny L. Experimental Lung Research, Vol. 30, Issue 1 https://doi.org/10.1080/01902140490252812	journal	January 2004
Fusion Inhibitory Lipopeptides Engineered for Prophylaxis of Nipah Virus in Primates Mathieu, Cyrille; Porotto, Matteo; Figueira, Tiago N. The Journal of Infectious Diseases, Vol. 218, Issue 2 https://doi.org/10.1093/infdis/jiy152	journal	March 2018
Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections Steenbergen, Judith N.; Alder, Jeff; Thorne, Grace M. Journal of Antimicrobial Chemotherapy, Vol. 55, Issue 3 https://doi.org/10.1093/jac/dkh546	journal	March 2005
Viral Entry Inhibitors Targeted to the Membrane Site of Action Porotto, Matteo; Yokoyama, Christine C.; Palermo, Laura M. Journal of Virology, Vol. 84, Issue 13 https://doi.org/10.1128/JVI.00135-10	journal	July 2010
Human Parainfluenza Virus Infection of the Airway Epithelium: Viral Hemagglutinin-Neuraminidase Regulates Fusion Protein Activation and Modulates Infectivity Palermo, Laura M.; Porotto, Matteo; Yokoyama, Christine C. Journal of Virology, Vol. 83, Issue 13 https://doi.org/10.1128/JVI.00475-09	journal	July 2009
Molecular Determinants of Antiviral Potency of Paramyxovirus Entry Inhibitors Porotto, M.; Carta, P.; Deng, Y. Journal of Virology, Vol. 81, Issue 19 https://doi.org/10.1128/JVI.01181-07	journal	October 2007
In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence Figueira, T. N.; Palermo, L. M.; Veiga, A. S. Journal of Virology, Vol. 91, Issue 1 https://doi.org/10.1128/JVI.01554-16	journal	January 2017
Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides Mathieu, C.; Huey, D.; Jurgens, E. Journal of Virology, Vol. 89, Issue 2 https://doi.org/10.1128/JVI.02417-14	journal	January 2015
Infection of Ciliated Cells by Human Parainfluenza Virus Type 3 in an In Vitro Model of Human Airway Epithelium Zhang, L.; Bukreyev, A.; Thompson, C. I. Journal of Virology, Vol. 79, Issue 2 https://doi.org/10.1128/JVI.79.2.1113-1124.2005	journal	December 2004
Adaptation of Human Parainfluenza Virus to Airway Epithelium Reveals Fusion Properties Required for Growth in Host Tissue Palmer, Samantha G.; Porotto, Matteo; Palermo, Laura M. mBio, Vol. 3, Issue 3 https://doi.org/10.1128/mBio.00137-12	journal	July 2012
Features of Circulating Parainfluenza Virus Required for Growth in Human Airway Palermo, Laura M.; Uppal, Manik; Skrabanek, Lucy mBio, Vol. 7, Issue 2 https://doi.org/10.1128/mBio.00235-16	journal	May 2016
Viral Entry Properties Required for Fitness in Humans Are Lost through Rapid Genomic Change during Viral Isolation Iketani, Sho; Shean, Ryan C.; Ferren, Marion mBio, Vol. 9, Issue 4 https://doi.org/10.1128/mBio.00898-18	journal	September 2018
Mechanisms of Virus Membrane Fusion Proteins Kielian, Margaret Annual Review of Virology, Vol. 1, Issue 1 https://doi.org/10.1146/annurev-virology-031413-085521	journal	November 2014
A General Strategy to Endow Natural Fusion-protein-Derived Peptides with Potent Antiviral Activity Pessi, Antonello; Langella, Annunziata; Capitò, Elena PLoS ONE, Vol. 7, Issue 5 https://doi.org/10.1371/journal.pone.0036833	journal	May 2012
Inhibition of Nipah Virus Infection In Vivo: Targeting an Early Stage of Paramyxovirus Fusion Activation during Viral Entry Porotto, Matteo; Rockx, Barry; Yokoyama, Christine C. PLoS Pathogens, Vol. 6, Issue 10 https://doi.org/10.1371/journal.ppat.1001168	journal	October 2010
Updated Guidance for Palivizumab Prophylaxis Among Infants and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Infection No authors listed Pediatrics, Vol. 134, Issue 2 https://doi.org/10.1542/peds.2014-1666	journal	August 2014
Paramyxovirus Fusion and Entry: Multiple Paths to a Common End Chang, Andres; Dutch, Rebecca E. Viruses, Vol. 4, Issue 4 https://doi.org/10.3390/v4040613	journal	April 2012

Cited By (2)

Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy Marcink, T. C.; Yariv, E.; Rybkina, K. mBio, Vol. 11, Issue 1 https://doi.org/10.1128/mbio.03203-19	journal	February 2020
Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition Aggarwal, Megha; Plemper, Richard K. Viruses, Vol. 12, Issue 3 https://doi.org/10.3390/v12030342	journal	March 2020

Similar Records

Structure of the parainfluenza virus 5 F protein in its metastable, prefusion conformation

Journal Article · Sun Mar 07 23:00:00 EST 2010 · Nature · OSTI ID:1007693

Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development

Journal Article · Mon Feb 03 23:00:00 EST 2025 · Journal of Virology · OSTI ID:2522033

Elevated temperature triggers human respiratory syncytial virus F protein six-helix bundle formation

Journal Article · Tue Jan 19 23:00:00 EST 2010 · Virology · OSTI ID:21357583

Related Subjects

60 APPLIED LIFE SCIENCES
hydrophobicity
infectious diseases
inhibition
inhibitors
peptides and proteins

Dual Inhibition of Human Parainfluenza Type 3 and Respiratory Syncytial Virus Infectivity with a Single Agent

Citation Formats

References (34)

Cited By (2)

Similar Records

Related Subjects