NOVEL-ANTI-INFECTIVE STRATEGY AGAINST INFLUENZA VIRUS AND S. AUREUS COINFECTIONS

• US 20170080045A1
• Filed: 05/18/2015
• Published: 03/23/2017
• Est. Priority Date: 05/16/2014
• Status: Active Grant

• Current Assignee: Atriva Therapeutics GmbH
• Original Assignee: Atriva Therapeutics GmbH
• Inventors: Ehrhardt, Christina, Ludwig, Stephan
• Granted Patent: US 10,456,440 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: C12Q 1/18 Testing for antimicrobial activity of a material
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to MEK inhibitor, p38 inhibitor and/or NFκB inhibitor for use in a method for the prophylaxis and/or treatment of a co-infection comprising a bacterial infection and an influenza virus infection or a bacterial infection alone. Also provided are compositions comprising such inhibitors for use in the prophylaxis and/or treatment of a co-infection comprising a bacterial infection and an influenza virus infection or a bacterial infection alone. In addition an in vitro test system, wherein the test system comprises cultured cells infected with an influenza virus and a bacterium or with a bacterium alone is provided.

Claims

1. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use in a method for the prophylaxis and/or treatment of a co-infection comprising a bacterial infection and an influenza virus infection.

3. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 1 or 2, wherein the bacterial infection is mediated by a bacterium selected from the group consisting of Staphylococcaceae, Streptococcaceae, Legionellaceae, Pseudomonadaceae, Chlamydiaceae, Mycoplasmataceae, Enterobacteriaceae, Pseudomonadales and/or Pasteurellaceae.

4. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claim 1 or 3, wherein the influenza virus infection is mediated by influenza A virus or influenza B virus.

5. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 4, wherein the influenza A virus is H1N1, H2N2, H3N2, H6N1, H7N7, H7N9, H9N2 H10N7, H10N8 or H5N1, preferably H3N2, H5N1, H1N1 and H7N9.

6. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1-5, wherein the MEK inhibitor is selected from the group consisting of U0126, PLX-4032, AZD6244, AZD8330, AS-703026, GSK-1120212, RDEA-119, RO-5126766, RO-4987655, CI-1040, PD-0325901, GDC-0973, TAK-733, PD98059, ARRY-438162, PF-3644022 and PD184352, preferably AZD8330, GSK-1120212, U0126, GDC-0973, CI-1040, PD0325901, ARRY-438162, PF-3644022 and AZD6244.

7. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1-6, wherein the p38 inhibitor is selected from the group consisting of SB202190, LY2228820, CAY10571, SB 203580, Tie2 Kinase Inhibitor, 2-(4-Chlorophenyl)-4-(fluorophenyl)-5-pyridin-4-yl-1,2-dihydropyrazol-3-one, CGH 2466, SB220025, Antibiotic LL Z1640-2, TAK 715, SB202190 hydrochloride, SKF 86002, AMG548, CMPD-1, EO 1428, JX 401, ML 3403, RWJ 67657, SB 202190, SB 203580, SB 203580 hydrochloride, SB 239063, SCIO 469, SX 011, TAK 715, Pamapimod, Losmapimod (GW856553), Dilmapimod (SB681323), VX 702, VX 745, Doramapimod (BIRB

     796), BMS-582949, ARRY-797, PH797804 preferably VX-702, SB202190, Pamapimod, Losmapimod (GW856553), Dilmapimod (SB681323), Doramapimod (BIRB

     796), BMS-582949, ARRY-797, PH797804 and SCIO-469.

8. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1-7, wherein the NFκ

B inhibitor is selected from the group consisting of LASAG, SC75741, MG 132, TPCA-1, PCTC, IMD 0354, Luteolin, Caffeic acid phenethyl ester, Cardamonin, PF 184, IKK 16, SC 514, Withaferin A, Arctigenin, Bay 11-7085, PSI, PR 39, Ro 106-9920, Bay 11-7821, ML-130, Celastrol, Tanshinone IIA, HU 211, Gliotoxin, CID 2858522, Honokiol, Andrographolide, 10Z-Hymenialdisine, ACHP, Pristimerin, Sulfasalazine, ML 120B dihydrochloride, Amlexanox, 9-Methylstreptimidone, N-Stearoyl phytosphingosine, 2-(1,8-naphthyridin-2-yl)-Phenol, 5-Aminosalicylic acid, BAY 11-7085, Ethyl 3,4-Dihydroxycinnamate, Helanalin, NE-KB Activation Inhibitor II, JSH-23, Glucocorticoid Receptor Modulator, CpdA, PPM-18, ASA, Pyrrolidinedithiocarbamic acid ammonium salt, (R)-MG132, SC75741, Rocaglamide, Sodium salicylate, QNZ, PS-1145, CAY10512, bortezomib, salsalate, resveratrol, deoxyspergualin, sulindac, thalidomide, AGRO-100, CHS 828 and/or Curcumin, preferably, bortezomib, curcumin, ASA, salsalate, resveratrol, sodium salicylate, LASAG, SC75741, deoxyspergualin, sulindac, thalidomide, AGRO-100 and/or CHS 828.

9. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1-8, wherein the MEK inhibitor is combined with another MEK inhibitor, the p38 inhibitor and/or the NFκ

B inhibitor;

the p38 inhibitor is combined with another p38 inhibitor, the MEK inhibitor and/or the NFκ

B inhibitor or the NFκ

B inhibitor is combined with another NFκ

B inhibitor, the p38 inhibitor and/or the MEK inhibitor.

10. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1, 3-9, wherein the MEK inhibitor, the p38 inhibitor and/or the NFκ

B inhibitor are combined with one or more inhibitors targeting the influenza virus and/or the bacterium.

11. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1-10, wherein the MEK inhibitor, the p38 inhibitor and/or the NFκ

B inhibitor are combined with one or more inhibitors targeting the bacterium.

12. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 10, wherein the MEK inhibitor, the p38 inhibitor and/or the NFκ

B inhibitor is/are administered contemporaneously, previously or subsequently to the one or more inhibitors targeting the influenza virus and/or the bacterium.

13. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 10 or 12, wherein the one or more inhibitors targeting the influenza virus is a neuraminidase inhibitor, preferably oseltamivir phosphate, zanamivir, oseltamivir or peramivir.

14. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 10 or 12, wherein the one or more inhibitors targeting the influenza virus is a compound targeting an ion channel protein (M2), preferably amantadine and/or rimantadine.

15. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 10 or 12, wherein the one or more inhibitors targeting the influenza virus is a compound targeting polymerase or endonuclease activity via interfering with a component of the viral polymerase complex, PB1, PB2, PA or NP, preferably NP blocker Nucleozin or polymerase inhibitor T-705.

16. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 10-15, wherein the one or more inhibitor targeting the bacterium is an antibiotic, preferably Gentamicin, Rifampicin, Lysosthaphin, Erythromycin, Levofloxacin Vancomycin, Teicoplanin, Penicillin and Oxacillin.

17. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1-16 in a subject, preferably a vertebrate.

18. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to any of claims 1, 3-17, wherein the MEK inhibitor, the p38 inhibitor and/or the NFκ

B inhibitor reduces both the viral and bacterial infection, when contacting it/them with an in vitro test system, wherein the test system comprises cultured cells infected with

a) an influenza virus and

b) a bacterium

when compared to the in vitro test system before the contacting.

19. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use according to claim 18, wherein the reduction of the viral infection is a reduction in plaque forming units (pfu)/ml and the reduction in the bacterial infection is a reduction in colony forming units (CFU)/ml.

2. MEK inhibitor, p38 inhibitor and/or NFκ

B inhibitor for use in a method for the prophylaxis and/or treatment of a bacterial infection.

20. A composition comprising a MEK inhibitor, a p38 inhibitor and/or a NFκ

B inhibitor for use in a method for the prophylaxis and/or treatment of a co-infection comprising a bacterial infection and an influenza virus infection.

21. A composition comprising a MEK inhibitor, a p38 inhibitor and/or a NFκ

B inhibitor for use in a method for the prophylaxis and/or treatment of a bacterial infection.

22. A composition comprising a MEK inhibitor, a p38 inhibitor and/or a NFκ

B inhibitor and one or more inhibitors targeting the influenza virus and/or the bacterium for use in a method for the prophylaxis and/or treatment of a co-infection comprising a bacterial infection and an influenza virus infection.

23. A composition comprising a MEK inhibitor, a p38 inhibitor and/or a NFκ

B inhibitor and one or more inhibitors targeting the bacterium for use in a method for the prophylaxis and/or treatment of a bacterial infection.

24. In vitro test system, wherein the test system comprises cultured cells infected with

a) an influenza virus and

b) a bacterium

25. Use of the in vitro test system of claim 24 for the determination of inhibitors effective in reducing a coinfection comprising a bacterial infection and an influenza virus infection.

26. A method for detecting molecules effective in the prophylaxis and/or treatment of a co-infection comprising a bacterial infection and an influenza virus infection comprising contacting the in vitro test system as defined in claim 24 with a compound of interest, wherein the compound of interest reduces both the viral and bacterial infection, compared to the in vitro test system before the contacting.

27. The use of claim 25 or the method of claim 26, wherein the reduction of the viral infection is a reduction in plaque forming units (pfu)/ml and the reduction in the bacterial infection is a reduction in colony forming units (CFU)/ml.

29. Use of the in vitro test system of claim 24 and of claim 28 for the examination of innate host cell responses, which optionally includes examination of the level of signal transduction, resulting cytokine and chemokine expression, induction of apoptosis and necrosis and/or redox hemostasis regulating health and disease.

30. Use of the in vitro test system of claim 29 for the determination of inhibitors effective in reducing a bacterial infection.

31. A method for detecting molecules effective in the prophylaxis and/or treatment a bacterial infection comprising contacting the in vitro test system as defined in claim 29 with a compound of interest, wherein the compound o f interest reduces the bacterial infection, compared to the in vitro test system before the contacting.

28. In vitro test system, wherein the in vitro test system comprises cultured cells infected with a bacterium.

32. A cultured cell infected with an influenza virus and a bacterium.

33. A cultured cell infected with a bacterium.