The Molecular Basis of the Specific Anti-influenza Action of Amantadine

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1985 Nov 1

PMID 4065098

Citations 306

Authors

A J Hay

A J Wolstenholme

J J Skehel

M H Smith

Affiliations

Soon will be listed here.

Abstract

Amantadine (1-aminoadamantane hydrochloride) is effective in the prophylaxis and treatment of influenza A infections. In tissue culture this selective, strain-specific antiviral activity occurs at relatively low concentrations (5 microM or less), which inhibit either the initiation of infection or virus assembly. The data reported here demonstrate that the basis of these actions is similar and resides in the virus-coded M2 membrane protein, the product of a spliced transcript of RNA segment 7. Mutations which confer resistance to amantadine are restricted to four amino acids within a hydrophobic sequence, indicating that the drug is targetted against the putative membrane-associated portion of the molecule. The influence of the virus haemagglutinin on the amantadine sensitivity of virus strains implies that the drug may interfere with interactions between these two virus proteins.

Citing Articles

Molecular biophysics and inhibition mechanism of influenza virus A M2 viroporin by adamantane-based drugs - Challenges in designing antiviral agents.

Georgiou K, Kolokouris D, Kolocouris A J Struct Biol X. 2025; 11:100122.

PMID: 40060197 PMC: 11889636. DOI: 10.1016/j.yjsbx.2025.100122.

Phlorotannin-Rich Seaweed Extract Inhibits Influenza Infection.

Mega D, Sharma P, Kipar A, Hetzel U, Bramwell C, Merritt A Viruses. 2025; 16(12.

PMID: 39772226 PMC: 11680388. DOI: 10.3390/v16121919.

Drug resistance and possible therapeutic options against influenza A virus infection over past years.

Asif Raza M, Ashraf M Arch Microbiol. 2024; 206(12):458.

PMID: 39499323 DOI: 10.1007/s00203-024-04181-3.

Activation of the Influenza B M2 Proton Channel (BM2).

Yue Z, Wu J, Teng D, Wang Z, Voth G Biochemistry. 2024; 63(22):3011-3019.

PMID: 39488842 PMC: 11580745. DOI: 10.1021/acs.biochem.4c00607.

Activation of the influenza B M2 proton channel (BM2).

Yue Z, Wu J, Teng D, Wang Z, Voth G bioRxiv. 2024; .

PMID: 39091734 PMC: 11291123. DOI: 10.1101/2024.07.26.605324.

References

WALLBANK A, Matter R, Klinikowski N . 1-Adamantanamine hydrochloride: inhibition of Rous and Esh Sarcoma viruses in cell culture. Science. 1966; 152(3730):1760-1. DOI: 10.1126/science.152.3730.1760. View

PORTERFIELD J . A simple plaque-inhibition test for the study of arthropod-borne viruses. Bull World Health Organ. 1960; 22:373-80. PMC: 2555326. View

Hay A . Studies on the formation of the influenza virus envelope. Virology. 1974; 60(2):398-418. DOI: 10.1016/0042-6822(74)90335-3. View

Appleyard G, MABER H . A plaque assay for the study of influenza virus inhibitors. J Antimicrob Chemother. 1975; 1(4 Suppl):49-53. DOI: 10.1093/jac/1.suppl_4.49. View

Appleyard G . Amantadine-resistance as a genetic marker for influenza viruses. J Gen Virol. 1977; 36(2):249-55. DOI: 10.1099/0022-1317-36-2-249. View

Skehel J, Hay A, Armstrong J . On the mechanism of inhibition of influenza virus replication by amantadine hydrochloride. J Gen Virol. 1978; 38(1):97-110. DOI: 10.1099/0022-1317-38-1-97. View

SANGER F, Nicklen S, Coulson A . DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977; 74(12):5463-7. PMC: 431765. DOI: 10.1073/pnas.74.12.5463. View

Hay A, Kennedy N, Skehel J, Appleyard G . The matrix protein gene determines amantadine-sensitivity of influenza viruses. J Gen Virol. 1979; 42(1):189-91. DOI: 10.1099/0022-1317-42-1-189. View

Lubeck M, SCHULMAN J, Palese P . Susceptibility of influenza A viruses to amantadine is influenced by the gene coding for M protein. J Virol. 1978; 28(3):710-6. PMC: 525794. DOI: 10.1128/JVI.28.3.710-716.1978. View

10.

Porter A, Barber C, Carey N, Hallewell R, Threlfall G, Emtage J . Complete nucleotide sequence of an influenza virus haemagglutinin gene from cloned DNA. Nature. 1979; 282(5738):471-7. DOI: 10.1038/282471a0. View

11.

Scholtissek C, Faulkner G . Amantadine-resistant and -sensitive influenza A strains and recombinants. J Gen Virol. 1979; 44(3):807-15. DOI: 10.1099/0022-1317-44-3-807. View

12.

Helenius A, Kartenbeck J, Simons K, Fries E . On the entry of Semliki forest virus into BHK-21 cells. J Cell Biol. 1980; 84(2):404-20. PMC: 2110562. DOI: 10.1083/jcb.84.2.404. View

13.

Winter G, Fields S . Cloning of influenza cDNA ino M13: the sequence of the RNA segment encoding the A/PR/8/34 matrix protein. Nucleic Acids Res. 1980; 8(9):1965-74. PMC: 324050. DOI: 10.1093/nar/8.9.1965. View

14.

Oxford J, Galbraith A . Antiviral activity of amantadine: a review of laboratory and clinical data. Pharmacol Ther. 1980; 11(1):181-262. DOI: 10.1016/0163-7258(80)90072-8. View

15.

Lamb R, Lai C, Choppin P . Sequences of mRNAs derived from genome RNA segment 7 of influenza virus: colinear and interrupted mRNAs code for overlapping proteins. Proc Natl Acad Sci U S A. 1981; 78(7):4170-4. PMC: 319750. DOI: 10.1073/pnas.78.7.4170. View

16.

Yoshimura A, Kuroda K, Kawasaki K, Yamashina S, Maeda T, Ohnishi S . Infectious cell entry mechanism of influenza virus. J Virol. 1982; 43(1):284-93. PMC: 256119. DOI: 10.1128/JVI.43.1.284-293.1982. View

17.

Dolin R, Reichman R, Madore H, Maynard R, Linton P . A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection. N Engl J Med. 1982; 307(10):580-4. DOI: 10.1056/NEJM198209023071002. View

18.

McCauley J, Mahy B, Inglis S . Nucleotide sequence of fowl plague virus RNA segment 7. J Gen Virol. 1982; 58 Pt 1:211-5. DOI: 10.1099/0022-1317-58-1-211. View

19.

Helenius A, Marsh M, White J . Inhibition of Semliki forest virus penetration by lysosomotropic weak bases. J Gen Virol. 1982; 58 Pt 1:47-61. DOI: 10.1099/0022-1317-58-1-47. View

20.

Patel T, Millican T, Bose C, Titmas R, Mock G, Eaton M . Improvements to solid phase phosphotriester synthesis of deoxyoligonucleotides. Nucleic Acids Res. 1982; 10(18):5605-20. PMC: 320910. DOI: 10.1093/nar/10.18.5605. View