A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo.

Animals Antiviral Agents / administration & dosage Humans Influenza A Virus, H1N1 Subtype / drug effects Influenza A Virus, H3N2 Subtype / drug effects Influenza, Human / drug therapy Lectins / administration & dosage Male Mice Musa / chemistry Mutation Plant Proteins / administration & dosage Protein Engineering Virus Internalization / drug effects
antiviral hemagglutinin influenza virus lectin membrane fusion

Journal

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876

Informations de publication

Date de publication:
28 01 2020
Historique:
pubmed: 15 1 2020
medline: 2 6 2020
entrez: 15 1 2020
Statut: ppublish

Résumé

There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus-endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.

Identifiants

DOI: 10.1073/pnas.1915152117 PMID: 31932446 PMC: PMC6995028
pubmed: 31932446
pii: 1915152117
doi: 10.1073/pnas.1915152117
pmc: PMC6995028
doi:

Substances chimiques

Antiviral Agents 0
Lectins 0
Plant Proteins 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2122-2132

Subventions

Organisme : NIAID NIH HHS
ID : T32 AI007528
Pays : United States
Organisme : NHLBI NIH HHS
ID : DP2 HL123229
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL117976
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM145304
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007863
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL144805
Pays : United States
Organisme : NIAID NIH HHS
ID : F31 AI136615
Pays : United States

Informations de copyright

Copyright © 2020 the Author(s). Published by PNAS.

Déclaration de conflit d'intérêts

Competing interest statement: D.M.M. is an inventor on a patent for H84T BanLec and the founder of the company Virule, which aims to commercialize H84T BanLec.

Références

Int Arch Allergy Immunol. 1992;97(1):17-24
pubmed: 1582693
Cell. 2016 Jul 28;166(3):596-608
pubmed: 27453466
Antiviral Res. 2008 Dec;80(3):266-71
pubmed: 18601954
Euro Surveill. 2008 Jan 31;13(5):null
pubmed: 18445375
Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):206-214
pubmed: 28003465
Antiviral Res. 1990 Oct-Nov;14(4-5):181-205
pubmed: 2088205
Org Biomol Chem. 2006 Mar 21;4(6):973-88
pubmed: 16525538
Clin Infect Dis. 2014 Jul 15;59(2):252-5
pubmed: 24748521
Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18153-8
pubmed: 15601777
mBio. 2018 May 15;9(3):
pubmed: 29764948
BMJ. 2009 Dec 08;339:b5106
pubmed: 19995812
Antiviral Res. 2012 Oct;96(1):13-20
pubmed: 22809862
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6108-13
pubmed: 10801978
J Biol Chem. 2010 Mar 19;285(12):8646-55
pubmed: 20080975
Sci Transl Med. 2017 Oct 18;9(412):null
pubmed: 29046433
Calcif Tissue Int. 1997 Feb;60(2):204-9
pubmed: 9056172
Antimicrob Agents Chemother. 2003 Aug;47(8):2518-25
pubmed: 12878514
JAMA. 2006 Feb 22;295(8):891-4
pubmed: 16456087
Lancet. 1998 Dec 5;352(9143):1831-2
pubmed: 9851393
Viruses. 2016 Sep 10;8(9):
pubmed: 27626438
Science. 2014 Oct 24;346(6208):473-7
pubmed: 25342804
MMWR Morb Mortal Wkly Rep. 2018 Feb 16;67(6):180-185
pubmed: 29447141
Sci Transl Med. 2012 Aug 15;4(147):147ra114
pubmed: 22896678
Influenza Other Respir Viruses. 2017 May;11(3):240-246
pubmed: 28146320
Methods Mol Biol. 2014;1200:93-100
pubmed: 25117227
Exp Cell Res. 1980 Jul;128(1):133-42
pubmed: 7408977
Annu Rev Immunol. 2003;21:547-78
pubmed: 12524383
J Biol Chem. 2014 Jun 13;289(24):16954-65
pubmed: 24790092
J Virol. 2000 Sep;74(18):8709-19
pubmed: 10954572
J Virol. 1990 Oct;64(10):5106-13
pubmed: 2168989
Antimicrob Agents Chemother. 1982 Sep;22(3):499-507
pubmed: 6182836
Curr Drug Targets. 2007 Oct;8(10):1116-25
pubmed: 17979671
Int J Biochem Cell Biol. 2008;40(12):2802-14
pubmed: 18598778
Clin Infect Dis. 2009 May 1;48(9):1254-6
pubmed: 19323631
Antimicrob Agents Chemother. 2008 Sep;52(9):3284-92
pubmed: 18625765
Influenza Other Respir Viruses. 2007 Jan;1(1):27-34
pubmed: 19453477
Emerg Infect Dis. 2009 Apr;15(4):552-60
pubmed: 19331731
J Virol. 2005 Oct;79(19):12416-24
pubmed: 16160169
Science. 2011 Aug 12;333(6044):850-6
pubmed: 21798894
Mol Biol Evol. 2007 Aug;24(8):1811-20
pubmed: 17522084
Lancet Infect Dis. 2012 Jan;12(1):36-44
pubmed: 22032844
Self Nonself. 2010 Oct;1(4):314-322
pubmed: 21487506
Med Res Rev. 2012 Mar;32(2):349-87
pubmed: 20577974
Nature. 2017 Sep 28;549(7673):538-542
pubmed: 28959962
PLoS Negl Trop Dis. 2019 Jul 29;13(7):e0007595
pubmed: 31356611
JAMA. 2009 Mar 11;301(10):1034-41
pubmed: 19255110
Biochemistry. 1984 Nov 20;23(24):5675-81
pubmed: 6098295
J Biol Chem. 1987 May 15;262(14):6500-5
pubmed: 3571268
FEBS Lett. 1985 Jun 17;185(2):299-305
pubmed: 3888674
Nature. 2015 Jan 8;517(7533):165-169
pubmed: 25567280
J Virol. 2004 Nov;78(22):12665-7
pubmed: 15507653
Pharm Res. 2004 Jul;21(7):1160-6
pubmed: 15290855
J Virol. 2015 Sep;89(17):8957-66
pubmed: 26085153
Viruses. 2014 Mar 14;6(3):1294-316
pubmed: 24638204
PLoS Pathog. 2017 Mar 13;13(3):e1006271
pubmed: 28288189
Cell. 2015 Oct 22;163(3):746-58
pubmed: 26496612
PLoS One. 2009 Dec 30;4(12):e8495
pubmed: 20041119
N Engl J Med. 2018 Sep 6;379(10):913-923
pubmed: 30184455

Auteurs

Evelyn M Covés-Datson (EM)

Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109.
Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109.
ORCID: 0000-0002-9299-0878

Steven R King (SR)

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
Therapeutic Systems Research Laboratories, Inc., Ann Arbor, MI 48108.

Maureen Legendre (M)

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.

Auroni Gupta (A)

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.

Susana M Chan (SM)

Therapeutic Systems Research Laboratories, Inc., Ann Arbor, MI 48108.
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109.

Emily Gitlin (E)

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.

Vikram V Kulkarni (VV)

Division of Internal Medicine, Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030.

Jezreel Pantaleón García (J)

Division of Internal Medicine, Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030.

Donald F Smee (DF)

Animal, Dairy and Veterinary Sciences Department, Utah State University, Logan, UT 84322.

Elke Lipka (E)

Therapeutic Systems Research Laboratories, Inc., Ann Arbor, MI 48108.

Scott E Evans (SE)

Division of Internal Medicine, Department of Pulmonary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030.

E Bart Tarbet (EB)

Animal, Dairy and Veterinary Sciences Department, Utah State University, Logan, UT 84322.

Akira Ono (A)

Department of Microbiology & Immunology, University of Michigan, Ann Arbor, MI 48109.

David M Markovitz (DM)

Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; dmarkov@med.umich.edu.
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109.
Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109.
Cancer Biology Program, University of Michigan, Ann Arbor, MI 48109.
ORCID: 0000-0003-3547-0849

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › A molecularly engineered antiviral banana...
Recherchemedicale.com › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › A molecularly engineered antiviral banana...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A molecularly engineered antiviral banana...
Recherchemedicale.com › Virus › Virus à ARN › Virus à ARN de polarité négative › Orthomyxoviridae › Influenzavirus A › Virus de la grippe A › Sous-type H1N1 du virus de la grippe A › A molecularly engineered antiviral banana...
Recherchemedicale.com › Virus › Virus à ARN › Virus à ARN de polarité négative › Orthomyxoviridae › Influenzavirus A › Virus de la grippe A › Sous-type H3N2 du virus de la grippe A › A molecularly engineered antiviral banana...
Recherchemedicale.com › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Grippe humaine › A molecularly engineered antiviral banana...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Lectines › A molecularly engineered antiviral banana...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A molecularly engineered antiviral banana...
Recherchemedicale.com › Eucaryotes › Viridiplantae › Streptophyta › Embryophyta › Tracheobionta › Magnoliopsida › Lilianae › Zingiberales › Musaceae › Musa › A molecularly engineered antiviral banana...
Recherchemedicale.com › Phénomènes génétiques › Variation génétique › Mutation › A molecularly engineered antiviral banana...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines végétales › A molecularly engineered antiviral banana...
Recherchemedicale.com › Techniques d'investigation › Techniques génétiques › Génie génétique › Ingénierie des protéines › A molecularly engineered antiviral banana...
Recherchemedicale.com › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Pénétration virale › A molecularly engineered antiviral banana...