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Metered dose inhaler containing aprotinin, a protease inhibitor, as a drug against Influenza

This study explores the use of a metered dose inhaler containing aprotinin, a protease inhibitor, as a potential treatment for influenza. The inhaler aims to suppress flu virus replication, reduce inflammation, and shorten the duration of symptoms in patients. Clinical benefits include a reduction in headache, throat pain, fever, and earlier discharge from the hospital.

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Metered dose inhaler containing aprotinin, a protease inhibitor, as a drug against Influenza

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  1. Metered dose inhaler containing aprotinin, a protease inhibitor, as a drug against Influenza Oleg Zhirnov, N.Bokova, E. Isaeva, I. Vorobjeva, O. Saphonova, N. Malyshev D.I.Ivanovsky Institute of Virology, Moscow, Russia Infectious clinics N1, Moscow, Russia

  2. Influenza virus HA PB1, PB2, PA NEP M2 NP M1 NA 100 nm

  3. Influenza virus proteolytic activation Non-active Virus Active virus Host proteases Uncleaved HA0 (75 kD) Cleaved HA1(55kD) + HA2(20kD)

  4. Signal peptide Signalase HA1(55kD) RBC S Cleavage Cleavage Site S IAP RBC Fusion peptide S S Anchor peptide HA0 (75kD) HA2 (20kD)

  5. Summary • Receptor protein HA locates as spike • on the virus surface. 2. HA is cleaved by host respiratory protease: HA0 (75 kD) → HA1 (55 kD) + HA2 (20 kD). 3. This HA cleavage activates virus infectivity. 4. The HA cleavage promotes infection spread.

  6. Host proteases ( Influenza activating proteases ) Serine proteases: Location: Transmembrane protease, serine 2 ( TMPRSS 2 ) Nasal, Tracheal, Bronchial, Lung (alveolocytes type II), Intestinal epithelium Transmembrane protease, serine 4 ( TMPRSS 4 ) Human airway trypsin-like protease ( HAT ) Matriptase

  7. Suggestion Suppression of Flu proteolytic activation with the help of specific protease inhibitor will reduce virus multiplication and provide therapeutic efficacy.

  8. Rational Decision Aprotinin has been selected for this aim as the officinal compound already approved for human usage.

  9. APROTININ STRUCTURE ( 58 a.a. polypeptide from bovine lungs ) Lys 15 K Met Lys15 A R C I P I G C G R G T R Y Y Y R A N K P F V P N Y F C F E S K N A T G L A A E C Q G K D F C C A D L C T G M P R R 50 N C N Primary Tertiary

  10. Clinical Forms of Aprotinin Usage Systemic injection form Local aerosol form ( AerusTM ) Nasal and oropharyngeal infusions and inhalations Intravenous infusion and injection 25,000 – 900,000 КIU/day 800 – 3,000 КIU/day

  11. Trachea-bronchial epithelium infected with human (a,c) and avian (b, d) Influenza Virus ( ciliated, secretory, basal cells + mucus blanket ) Matrosovich et al. 2004

  12. - + Apr HA0 HA1+NA HA2 108 105 Infectivity(pfu/ml) Aprotinin inhibits flu virus HA0 cleavage in Trachea-bronchial epithelium Мol. Wt. 75 кД 50 кД 20 кД Zhirnov et al. 2011 Antiviral Chem Chemother 21: 169-174

  13. Aprotinin inhibits replication of Influenza Virus H1N1pdm in Trachea-bronchial epithelium 10 8 6 Control Virus titer (lg pfu) 4 +APR 2 Hours post infection Zhirnov et al. 2011

  14. Summary: • Aprotinin inhibits influenza virus • НА0 → HA1+HA2 cleavage and suppresses • virus replication. • A second target of aprotinin is inhibition of • inflammation in infection locus.

  15. Duration of symptoms in Flu patients treated with aprotinin mini-inhaler Ingavirin Aprotinin Duration (Days) Fever Cough rhinorrhea Headache Weakness Chest pain Sore throat Zhirnov & Malyshev, 2014

  16. Viral loads in naso-pharyngeal washes in H1N1pdm patients treated with aprotinin MDI Ingavirin (Control) Aprotinin Number of washes(%) 106-104 103-101 <101 Viral genomes in ml of nasopharyngeal wash

  17. Clinical Benefits of Aerosolized Aprotinin Against Influenza • About two-fold reduction in duration • of headache, throat pain, hoarseness, • fever, earlier discharge from hospital. • Aprotinin inhalations were well tolerated • by patients and no adverse reactions • were observed.

  18. Aprotinin inhibits vicious cycle in Flu pathogenesis Virus activation Non-active virus Active virus Aprotinin (АERUS) Proteases Infection Primarily Infection locus Inflammation Aprotinin (АERUS) Proteases

  19. Benefits of Aprotinin usage against Flu • Aprotinin is a polyvalent drug effective against • many strains of Influenza A, B, and C viruses. • Aprotinin, as a host-targeted antiviral, will not • select resistance for influenza viruses. 3. Aprotinin has a binary therapeutic effect: (а) inhibits virus replication; (b) reduces inflammation in infection locus. • A local aerosol inhalation form of aprotinin is recommended against Influenza.

  20. Zhirnov O.P., Klenk H.D., Wright P.F. «Aprotinin and similar protease inhibitors as drugs against influenza» Antiviral Research v.92: 27-36 (2011) Zhirnov O.P., Malyshev N.A. «New in the treatment of influenza: a propellant metered dose inhaler containing aprotinin» Treating Doctor N1: 57-62 (2014) (Russian). zhirnov@inbox.ru

  21. Thanks for the Attention

  22. Victory Day May 5, 1945 !!! My father, Peter T. Zhirnov - a soldier of a 2-nd World War, is dedicated

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