Peptide-mediated Interference with Influenza A Virus Polymerase

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2007 May 12

PMID 17494067

Citations 59

Authors

Alexander Ghanem

Daniel Mayer

Geoffrey Chase

Werner Tegge

Ronald Frank

Georg Kochs

Adolfo Garcia-Sastre

Martin Schwemmle

Affiliations

Soon will be listed here.

Abstract

The assembly of the polymerase complex of influenza A virus from the three viral polymerase subunits PB1, PB2, and PA is required for viral RNA synthesis. We show that peptides which specifically bind to the protein-protein interaction domains in the subunits responsible for complex formation interfere with polymerase complex assembly and inhibit viral replication. Specifically, we provide evidence that a 25-amino-acid peptide corresponding to the PA-binding domain of PB1 blocks the polymerase activity of influenza A virus and inhibits viral spread. Targeting polymerase subunit interactions therefore provides a novel strategy to develop antiviral compounds against influenza A virus or other viruses.

Citing Articles

Antiviral strategies against influenza virus: an update on approved and innovative therapeutic approaches.

Bonomini A, Mercorelli B, Loregian A Cell Mol Life Sci. 2025; 82(1):75.

PMID: 39945883 PMC: 11825441. DOI: 10.1007/s00018-025-05611-1.

A Novel Peptide from VP1 of EV-D68 Exhibits Broad-Spectrum Antiviral Activity Against Human Enteroviruses.

Lin X, Sun Q, Cao Y, Li Z, Xu C, Liu J Biomolecules. 2024; 14(10).

PMID: 39456264 PMC: 11506774. DOI: 10.3390/biom14101331.

The PB2 I714S mutation influenced mammalian adaptation of the H3N2 canine influenza virus by interfering with nuclear import efficiency and RNP complex assembly.

Li X, Jia T, Wang K, Wang L, Zhou L, Li M Emerg Microbes Infect. 2024; 13(1):2387439.

PMID: 39139051 PMC: 11328605. DOI: 10.1080/22221751.2024.2387439.

Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome.

Ranum J, Ledwith M, Alnaji F, Diefenbacher M, Orton R, Sloan E Nucleic Acids Res. 2024; 52(6):3199-3212.

PMID: 38407436 PMC: 11014358. DOI: 10.1093/nar/gkae133.

Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome.

Ranum J, Ledwith M, Alnaji F, Diefenbacher M, Orton R, Sloan E bioRxiv. 2024; .

PMID: 38168266 PMC: 10760031. DOI: 10.1101/2023.12.12.570638.

References

Naffakh N, van der Werf S . Comparative analysis of the ability of the polymerase complexes of influenza viruses type A, B and C to assemble into functional RNPs that allow expression and replication of heterotypic model RNA templates in vivo. Virology. 1999; 265(2):342-53. DOI: 10.1006/viro.1999.0059. View

Ohtsu Y, Honda Y, Sakata Y, Kato H, Toyoda T . Fine mapping of the subunit binding sites of influenza virus RNA polymerase. Microbiol Immunol. 2002; 46(3):167-75. DOI: 10.1111/j.1348-0421.2002.tb02682.x. View

Vives E, Richard J, Rispal C, Lebleu B . TAT peptide internalization: seeking the mechanism of entry. Curr Protein Pept Sci. 2003; 4(2):125-32. DOI: 10.2174/1389203033487306. View

Hartlieb B, Modrof J, Muhlberger E, Klenk H, Becker S . Oligomerization of Ebola virus VP30 is essential for viral transcription and can be inhibited by a synthetic peptide. J Biol Chem. 2003; 278(43):41830-6. DOI: 10.1074/jbc.M307036200. View

Poole E, Elton D, Medcalf L, Digard P . Functional domains of the influenza A virus PB2 protein: identification of NP- and PB1-binding sites. Virology. 2004; 321(1):120-33. DOI: 10.1016/j.virol.2003.12.022. View

Pilger B, Cui C, Coen D . Identification of a small molecule that inhibits herpes simplex virus DNA Polymerase subunit interactions and viral replication. Chem Biol. 2004; 11(5):647-54. DOI: 10.1016/j.chembiol.2004.01.018. View

Palese P, Compans R . Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. J Gen Virol. 1976; 33(1):159-63. DOI: 10.1099/0022-1317-33-1-159. View

Hay A, Wolstenholme A, Skehel J, Smith M . The molecular basis of the specific anti-influenza action of amantadine. EMBO J. 1985; 4(11):3021-4. PMC: 554613. DOI: 10.1002/j.1460-2075.1985.tb04038.x. View

Fawell S, Seery J, Daikh Y, Moore C, Chen L, Pepinsky B . Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci U S A. 1994; 91(2):664-8. PMC: 43009. DOI: 10.1073/pnas.91.2.664. View

10.

Perez D, Donis R . A 48-amino-acid region of influenza A virus PB1 protein is sufficient for complex formation with PA. J Virol. 1995; 69(11):6932-9. PMC: 189611. DOI: 10.1128/JVI.69.11.6932-6939.1995. View

11.

De Clercq E . Antivirals and antiviral strategies. Nat Rev Microbiol. 2004; 2(9):704-20. PMC: 7097272. DOI: 10.1038/nrmicro975. View

12.

Pleschka S, Jaskunas R, Engelhardt O, Zurcher T, Palese P, Garcia-Sastre A . A plasmid-based reverse genetics system for influenza A virus. J Virol. 1996; 70(6):4188-92. PMC: 190316. DOI: 10.1128/JVI.70.6.4188-4192.1996. View

13.

Biswas S, Nayak D . Influenza virus polymerase basic protein 1 interacts with influenza virus polymerase basic protein 2 at multiple sites. J Virol. 1996; 70(10):6716-22. PMC: 190714. DOI: 10.1128/JVI.70.10.6716-6722.1996. View

14.

Gonzalez S, Zurcher T, Ortin J . Identification of two separate domains in the influenza virus PB1 protein involved in the interaction with the PB2 and PA subunits: a model for the viral RNA polymerase structure. Nucleic Acids Res. 1996; 24(22):4456-63. PMC: 146260. DOI: 10.1093/nar/24.22.4456. View

15.

Jambrina E, Barcena J, Uez O, Portela A . The three subunits of the polymerase and the nucleoprotein of influenza B virus are the minimum set of viral proteins required for expression of a model RNA template. Virology. 1997; 235(2):209-17. DOI: 10.1006/viro.1997.8682. View

16.

Dostmann W, Nickl C, Thiel S, Tsigelny I, Frank R, Tegge W . Delineation of selective cyclic GMP-dependent protein kinase Ialpha substrate and inhibitor peptides based on combinatorial peptide libraries on paper. Pharmacol Ther. 1999; 82(2-3):373-87. DOI: 10.1016/s0163-7258(98)00063-1. View

17.

Gabriel G, Dauber B, Wolff T, Planz O, Klenk H, Stech J . The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci U S A. 2005; 102(51):18590-5. PMC: 1317936. DOI: 10.1073/pnas.0507415102. View

18.

Loregian A, Coen D . Selective anti-cytomegalovirus compounds discovered by screening for inhibitors of subunit interactions of the viral polymerase. Chem Biol. 2006; 13(2):191-200. DOI: 10.1016/j.chembiol.2005.12.002. View

19.

Perez D, Donis R . Functional analysis of PA binding by influenza a virus PB1: effects on polymerase activity and viral infectivity. J Virol. 2001; 75(17):8127-36. PMC: 115057. DOI: 10.1128/jvi.75.17.8127-8136.2001. View

20.

Maroun R, Gayet S, Benleulmi M, Porumb H, Zargarian L, Merad H . Peptide inhibitors of HIV-1 integrase dissociate the enzyme oligomers. Biochemistry. 2001; 40(46):13840-8. DOI: 10.1021/bi011328n. View