US-20260124215-A1 - METHODS OF TREATMENT OF INTESTINAL INFECTIONS

Abstract

The present invention relates to compositions and methods for treating or preventing infections, in particular infections by intracellular parasites such as Cryptosporidium spp. The present invention also relates to compositions and methods for treating or preventing viral or bacterial infections, in particular intestinal infections such as those caused by rotavirus and Salmonella spp. Infections. The methods comprise administration of, and the compositions comprise, a farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, such as lapaquistat.

Inventors

• Adam SATERIALE
• Noorul Bishara MARZOOK

Assignees

• THE FRANCIS CRICK INSTITUTE LIMITED

Dates

Publication Date

20260507

Application Date

20231004

Priority Date

20221004

Claims (20)

1. 1 . A farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a parasitic infection.
2. 2 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to claim 1 , wherein the parasitic infection is an infection by an intracellular parasite which is incapable of endogenous cholesterol biosynthesis.
3. 3 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to claim 1 or claim 2 , wherein the parasitic infection is an infection by an intracellular parasite which is incapable of endogenous squalene synthesis.
4. 4 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any preceding claim , wherein the parasitic infection is an infection by an intracellular parasite which does not express an endogenous squalene synthase.
5. 5 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any preceding claim , wherein the parasitic infection is an infection by an intracellular parasite which is an obligate intracellular parasite.
6. 6 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any preceding claim , wherein the parasitic infection is an infection by a parasite which is in the order of Eucoccidiorida, preferably in the suborder of Eimeriorina.
7. 7 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any preceding claim , wherein the parasitic infection is an infection by a Cryptosporidium spp.
8. 8 . A farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a Cryptosporidium infection.
9. 9 . A farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a viral infection.
10. 10 . A farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a rotavirus infection.
11. 11 . A farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a bacterial infection.
12. 12 . A farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a Salmonella infection.
13. 13 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any preceding claim , wherein the FDFT1 inhibitor has the following structure:
14. 14 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any preceding claim , wherein the FDFT1 inhibitor is lapaquistat.
15. 15 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any one of claims 1-12 , wherein the FDFT1 inhibitor is YM-53601, or a pharmaceutically acceptable salt thereof.
16. 16 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any one of claims 1-12 , wherein the FDFT1 inhibitor has the following structure:
17. 17 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any preceding claim , wherein the FDFT1 inhibitor is administered simultaneously, sequentially or separately with one or more other drugs used in the treatment or prophylaxis of the parasitic infection or Cryptosporidium infection.
18. 18 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to claim 17 , wherein the one or more other drugs is formulated in a combined preparation with the FDFT1 inhibitor or pharmaceutically acceptable salt thereof.
19. 19 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to claim 17 or claim 18 , wherein the one or more other drugs comprises nitazoxanide, paromomycin or halofuginone.
20. 20 . The FDFT1 inhibitor or pharmaceutically acceptable salt thereof for use according to any one of claims 17-19 , wherein the one or more other drugs comprises nitazoxanide.

Description

FIELD OF THE INVENTION The present invention relates to compositions and methods for treating clinical conditions arising from intestinal infections, in particular parasitic diseases such as those caused by Cryptosporidium spp. The present invention also relates to compositions and methods for treating clinical conditions arising from viral and bacterial infections, in particular intestinal diseases such as those caused by rotavirus and Salmonella spp. infections. BACKGROUND The Cryptosporidium parasite is a leading cause of diarrheal illness in humans and livestock. In humans, immunocompromised patients and children bear a substantial burden of the disease. The only approved drug in humans is nitazoxanide, which has limited efficacy in malnourished and immunocompromised patients [1]. Complications from Cryptosporidium infection kills somewhere between 50-200K people per year (mostly children) and there is a strong correlation between early life cases and chronic malnutrition [2]. There are no vaccines available and there is a desperate need for more effective therapeutics to treat infection. Cryptosporidium is a eukaryotic pathogen that specifically infects epithelial cells within the host intestine. As an intracellular parasite, Cryptosporidium is entirely dependent on its host cell for nutrients and shelter while it grows and replicates. Replication by the parasite is both asexual (mitosis) and sexual (meiosis) and the latter is required for production of new oocysts, which are the transmissible form of the parasite. In order to identify the host genes and pathways that are essential for supporting parasite growth and development, the present inventors employed a high throughput microscopy-based CRISPR screen across the entire human genome. From this screen we identified the host gene FDFT1, or farnesyl-diphosphate farnesyltransferase 1, as essential for the parasite to grow and develop. Further, we identified two inhibitors of FDFT1, TAK-475 or lapaquistat, and YM-53601 that are capable of blocking Cryptosporidium growth and development. Lapaquistat is described in detail in U.S. Pat. No. 6,613,761B1, which is incorporated herein by reference. YM-53601 is described in detail in document [3], which is incorporated herein by reference. SUMMARY OF THE INVENTION The present invention provides a farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing an infection. In some embodiments, the infection is an infection by an intracellular pathogen which is incapable of endogenous cholesterol biosynthesis. In some embodiments, the infection is an infection by an intracellular pathogen which is incapable of endogenous squalene synthesis. In some embodiments, the infection is an infection by an intracellular pathogen which does not express an endogenous squalene synthase. The present invention provides a farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a parasitic infection. The inventors have surprisingly found that effective inhibition of parasite growth can be achieved by targeting the cholesterol biosynthesis pathway of the host (as opposed to cholesterol biosynthesis in the parasite), specifically by inhibiting FDFT1 (squalene synthase) activity. Lapaquistat is a suitable FDFT1 inhibitor which can be used to treat a parasitic infection (e.g., a Cryptosporidium infection) in accordance with the methods of the invention, as demonstrated in, e.g., Example 3. Because of the unique mechanism of action, it is expected that FDFT1 inhibition would also be an effective treatment against other pathogens that rely on host cells for cholesterol biosynthesis, in particular other intracellular pathogens that rely on host cells for cholesterol biosynthesis. In some embodiments, the parasitic infection is an infection by an intracellular parasite which is incapable of endogenous cholesterol biosynthesis. In some embodiments, the parasitic infection is an infection by an intracellular parasite which is incapable of endogenous squalene synthesis. In some embodiments, the parasitic infection is an infection by an intracellular parasite which does not express an endogenous squalene synthase. In some embodiments, the parasitic infection is an infection by an intracellular parasite which is an obligate intracellular parasite. In some embodiments, the parasitic infection is an infection by an intracellular parasite which is in the order of Eucoccidiorida, preferably in the suborder of Eimeriorina. Preferably, the parasite is a Cryptosporidium spp. The present invention also provides a farnesyl-diphosphate farnesyltransferase 1 (FDFT1) inhibitor, or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a Cryptosporidium infection. The present invention also provides a farnesyl-diphosphate farnesyltran