Anti-infective strategy against influenza virus and S. aureus coinfections

• US 10,456,440 B2
• Filed: 05/18/2015
• Issued: 10/29/2019
• Est. Priority Date: 05/16/2014
• Status: Active Grant

• Current Assignee: Atriva Therapeutics GmbH
• Original Assignee: Atriva Therapeutics GmbH
• Inventors: Ehrhardt, Christina, Ludwig, Stephan
• Primary Examiner(s): Blumel, Benjamin P
• Application Number:
  US15/310,836
• Publication Number:
  US 20170080045A1
• Time in Patent Office: 1,625 Days
• Field of Search: None
• 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. A method for inhibiting a Staphylococcus aureus infection and an influenza virus infection in a cell comprising contacting the cell with an effective amount of a MEK inhibitor, a p38 inhibitor and/or an NFκ

B inhibitor.

3. The method claim 1, wherein the influenza virus infection is mediated by influenza A virus or influenza B virus.

4. The method according to claim 3, wherein the influenza A virus is H1N1, H2N2, H3N2, H6N1, H7N7, H7N9, H9N2,H10N7, H10N8or H5N1.

5. The method according to claim 1 or 2, 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.

6. The method of claim 1 or 2, wherein the p38 inhibitor is selected from the group consisting of SB202190, LY2228820, CAY10571, SB203580, 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.

7. The method according to claim 1 or 2, 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.

8. The method according to claim 1, 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 Staphylococcus aureus.

10. The method according to claim 8 wherein the one or more inhibitors targeting the influenza virus is a neuraminidase inhibitor.

11. The method according to claim 8, wherein the one or more inhibitor(s) targeting the Staphylococcus aureus is an antibiotic.

12. The method according to claim 1 or 2, wherein the cell is a vertebrate cell.

13. The method according to claim 10, wherein the neuraminidase inhibitor is oseltamivir phosphate, zanamivir, oseltamivir or peramivir.

14. The method according to claim 11, wherein the antibiotic is Gentamicin, Rifampicin, Lysosthaphin, Erythromycin, Levofloxacin, Vancomycin, Teicoplanin, Penicillin or Oxacillin.

15. The method according to claim 12, wherein the vertebrate cell is a human cell.

2. A method for inhibiting a Staphylococcus aureus infection in a cell comprising contacting the cell with an effective amount of a MEK inhibitor, a p38 inhibitor and/or an NFκ

B inhibitor.

9. The method according to claim 2, wherein the MEK inhibitor, the p38 inhibitor and/or the NFκ

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