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EP-4735000-A1 - TREATMENT OF INFECTIONS CAUSED BY INTRACELLULAR PATHOGENS

EP4735000A1EP 4735000 A1EP4735000 A1EP 4735000A1EP-4735000-A1

Abstract

Compositions and methods for treating or preventing an infection by an intracellular pathogen in a subject in need thereof are provided.

Inventors

  • GAL-MOR, Ohad
  • ADANI, Boaz
  • MARGULIS, DAVID
  • MOTIEI, Leila
  • HAIM, Barr
  • KHRIESTO, Shurrush

Assignees

  • Sheba Impact Ltd.
  • Yeda Research and Development Co. Ltd

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A method of treating or preventing an infection by an intracellular pathogen in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound represented by Formula I, II, III, IV, V, VI or VII: Formula I wherein: n is 0 or 1 ; R 1 and R 2 are each independently selected from hydrogen and alkyl, preferably a lower alkyl of 1 to 4 carbon atoms in length, wherein at least one of R 1 and R 2 is said alkyl; R 3 -R 14 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, thiol, thioalkoxy, amine, cyano and nitro; R 15 -R 24 are each independently selected from hydrogen, alkyl, cycloalkyl, amine, halo, hydroxy, thiol, alkoxy, and thioalkoxy; and R 25 is selected from hydrogen, alkyl and cycloalkyl, wherein: R 30 and R 31 are each independently selected from hydrogen, alkyl and cycloalkyl; R 32 -R 36 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxy, alkoxy, thiol, thioalkoxy, amine, cyano and nitro, provided that at least one of R 32 -R 36 , preferably at least one of R 32 , R 34 and R 36 is halo; and A is selected from: wherein the curved line represents an attachment point to NR30-; and R 37 and R38 are each independently selected from hydrogen alkyl and cycloalkyl, wherein: R 40 -R 44 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, hydroxy, alkoxy, thiol, thioalkoxy, amine, provided that at least one of R 40 -R 44 , preferably R 40 , is a cycloalkyl; and R 45 -R 52 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, hydroxy, alkoxy, thiol, thioalkoxy, amine, provided that at least one of R 45 -R 50 is selected from hydroxy, thiol, alkoxy and thioalkoxy, Formula IV wherein: R 61 -R 64 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, thioalkoxy; R 65 and R66 are each independently selected from hydrogen, alkyl and cycloalkyl; R 67 -R 78 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol and thioalkoxy; and R 80 represents one or more (1, 2, 3, 4 or 5) substituents on the phenyl ring, or is absent, wherein each of these substituents, if present, is independently selected from alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, and thioalkoxy, wherein: R 80 and R 81 are each independently selected from hydrogen, alkyl and cycloalkyl; R82-R86 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, and thioalkoxy; R 87 -R 90 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, and thioalkoxy; R 91 -R 94 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, and thioalkoxy; and R 95 -R 98 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, and thioalkoxy, Formula VI wherein: R100 is hydrogen, alkyl or cycloalkyl; R 101 -R 105 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, thioalkoxy, heteroaryl, cyano, and nitro, wherein at least one of R 101 -R 105 , preferably R 101 , is aryl; R 106 -R 109 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol and thioalkoxy; R 110 -R 113 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol and thioalkoxy, or, alternatively, two of R 110 -R 113 form together a substituted or unsubstituted cyclic ring (alicyclic, heteroalicyclic, aryl or heteroaryl); and R 114 -R 117 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol and thioalkoxy, wherein: X is O, S or NR 120 ; R 119 and R 120 (if present) are each independently selected from hydrogen, alkyl or cycloalkyl; R 121 -R 125 are each independently selected from hydrogen, alkyl, cycloalkyl, aryl, halo, haloalkyl, amine, hydroxy, alkoxy, aryloxy, thioaryloxy, thiol, thioalkoxy, heteroaryl, cyano and nitro, or, alternatively or in addition, two of R 121 -R 125 form together a substituted or unsubstituted cyclic ring (alicyclic, heteroalicyclic, aryl or heteroaryl); and R 126 -R 129 are each independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, amine, hydroxy, alkoxy, thiol, thioalkoxy, heteroalicyclic, heteroaryl, and aryloxy, provided that at least one of R 121 -R 125 and at least one of R 126 -R 129 is other than hydrogen.
  2. 2. A method of inhibiting growth of an intracellular pathogen or invasion thereof into host cells, the method comprising contacting the pathogen with a therapeutically effective amount of a pharmaceutical composition comprising at least one compound represented by Formula I, II, III, IV, V, VI or VII as defined in claim 1.
  3. 3. A method of treating or preventing an infection by an intracellular pathogen in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound which induces programmed cell death (PCD) in host cells of said intracellular pathogen, thereby treating or preventing the infection.
  4. 4. A method of inhibiting growth of an intracellular pathogen or invasion thereof into host cells, the method comprising contacting the pathogen with a therapeutically effective amount of a pharmaceutical composition comprising a compound which induces PCD in host cells of said intracellular pathogen, thereby inhibiting growth of the intracellular pathogen or invasion thereof into host cells.
  5. 5. The method of any one of claims 1-4 being performed in vitro.
  6. 6. The method of any one of claims 1-4 being performed in vivo.
  7. 7. A method of identifying an agent against intracellular pathogens, the method comprising: (a) providing host cells infected with an intracellular pathogen genetically modified to express a reporter molecule under a cis-acting regulatory element of said intracellular pathogen; (b) contacting said host cells with an antibiotic to eliminate extracellular pathogens; (c) subjecting said host cells to a treatment with an agent; (d) measuring a reporter activity of said reporter molecule in presence and in absence of said agent, wherein a decrease in said reporter activity in the presence of said agent in comparison to an absence thereof is indicative that the agent can be used against intracellular pathogens.
  8. 8. The method of claim 7, wherein said cis-acting regulatory element is a promoter.
  9. 9. The method of claim 8, wherein said promoter comprises the ssek3 promoter.
  10. 10. The method of claim 7, further comprising determining viability of said host cells in the presence of said agent in comparison to an absence thereof, and wherein substantially the same viability is indicative that said agent is safe.
  11. 11. The method of any one of claims 7-10, wherein said host cells are epithelial cells.
  12. 12. A pharmaceutical composition comprising at least one compound represented by Formula I, II, III, IV, V, VI or VII as defined in claim 1 for use in treating or preventing an infection by an intracellular pathogen in a subject in need thereof.
  13. 13. A pharmaceutical composition comprising a compound which induces PCD in host cells of an intracellular pathogen for use in treating or preventing an infection by the intracellular pathogen in a subject in need thereof.
  14. 14. The method or composition for use of any one of claims 1-13, wherein said intracellular pathogen is selected from the group consisting of bacterial pathogen, viral pathogen, fungal pathogen and a protozoan pathogen.
  15. 15. The method or composition for use of any one of claims 1-14, wherein said intracellular pathogen comprises bacteria.
  16. 16. The method or composition for use of claim 15, wherein said bacteria is Gram positive or Gram negative.
  17. 17. The method or composition for use of claim 15 or 16, wherein said bacteria is of a genus selected from the group consisting of Listeria monocytogenes, Salmonella enterica serovars (e.g., Salmonella Typhi), Mycobacterium tuberculosis, Chlamydia trachomatis, Rickettsia species and Legionella pneumophila.
  18. 18. The method or composition for use of claim 15 or 16, wherein said bacteria comprises a vacuolar intracellular bacterium.
  19. 19. The method or composition for use of claim 15 or 16, wherein said bacteria comprises an intracellular cytosolic bacterium.
  20. 20. The method or composition for use of any one of claims 1, 3, 12 and 13, wherein said infection causes tuberculosis (TB), chlamydia, listeriosis, invasive salmonellosis, legionnaire’s disease, Rocky Mountain spotted fever (R. rickettsii) or typhus (R. prowazekii).

Description

TREATMENT OF INFECTIONS CAUSED BY INTRACELLULAR PATHOGENS RELATED APPLICATION/S This application claims the benefit of priority of U.S. Provisional Patent Application No. 63/523,687 filed on 28 June 2023, the contents of which are incorporated herein by reference in their entirety. FIELD AND BACKGROUND OF THE INVENTION The present invention, in some embodiments thereof, relates to treatment of infections caused by intracellular pathogens. Infectious diseases still pose a major threat to both human and animal populations. A recent study estimated that infections by antibacterial resistant pathogens claim 700,000 lives every year globally, with 10 million projected deaths in the year 20502. Moreover, the WHO and World Economic Forum recently declared that antibacterial resistance is the greatest risk to human health. Even now, many infectious diseases are difficult to treat, resulting in high-dose administration of antibacterials, unbearable toxicity, delay in effective treatment, and increased mortality due to multidrug resistant (MDR) infections 3. Importantly, this challenge is specifically prominent in the context of infections by intracellular bacterial pathogens. Intracellular bacterial pathogens invade host cells to establish an adapted replication niche, which facilitates their survival and dissemination. This compartment offers protection from the host's humoral immunity, sequestration from neutrophils, and access to nutrients that may be scarce extracellularly 4’ 5. As a result, intracellular bacterial pathogens have evolved to sophisticatedly manipulate host cells to access their preferred niches within targeted cells. After invasion, bacteria are contained within a plasma membrane-derived vacuole, such as phagosomes or endosomes. Vacuolar intracellular bacteria, like Salmonella enterica or Mycobacterium tuberculosis remain within modified vacuoles, while intracellular cytosolic bacteria, like Listeria monocytogenes or Shigella spp., rupture the vacuole and reside in the host cytosol4-7. Intracellular pathogens have co-evolved with hosts and developed a striking ability to manipulate and subvert multiple host functions and pathways to facilitate their survival and transmission. In general, the process by which intracellular bacteria hijack host cells can be divided into four distinct stages: adhesion, internalization, survival/prolif eration, and dissemination. Although different pathogens use distinct strategies to subvert host pathways, eliminating the replicative niche of pathogens by regulated cell death of host cells serves as a universal defense mechanism against a wide array of intracellular pathogens. Pathogen- associated molecular patterns (PAMPs) are sensed by pattern-recognition receptors (PRRs), leading to the activation of regulated lytic cell death, including pyroptosis and necroptosis, and a pro- inflammatory response. 5’ 8’ 9 This lytic form of cell death removes the replicative niche for intracellular pathogens by inducing the formation of large pores in the plasma membrane. This process releases highly inflammatory cytoplasmic contents, including proinflammatory cytokines and damage-associated molecular patterns (DAMPs), which recruit and activate immune cells to combat the infection 10. Although significant progress has been made in the last decades in our understanding of how intracellular pathogens interact with their hosts 11 , this group of pathogens remains a major clinical concern worldwide, and the gained knowledge has not been translated into new therapeutic approaches yet. This challenge has become even more pressing with the increasing prevalence of MDR strains that are often linked to a more severe disease outcome and more resistant strains that continue to emerge worldwide 10. Worrisomely, some of these bacteria are responsible for very important and common infectious diseases, including tuberculosis (TB), chlamydia, listeriosis, and invasive salmonellosis 12. Hence, there is an urgent need to develop novel and creative approaches to treat intracellular infections. Additional background art includes: Chandra et al. 2016 mSphere volume 1: issue 2 27. SUMMARY OF THE INVENTION According to an aspect of some embodiments of the present invention there is provided a method of treating or preventing an infection by an intracellular pathogen in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound represented by Formula I, II, III, IV, V, VI or VII, as described herein in any of the respective embodiments and any combination thereof. According to an aspect of some embodiments of the present invention there is provided a method of inhibiting growth of an intracellular pathogen or invasion thereof into host cells, the method comprising contacting the pathogen with a therapeutically effective amount of a pharmaceutical composition comprising at least one