US-20260124172-A1 - Use of cembrane-type diterpene compounds in the preparation of medicament for preventing or treating inflammasome mediated inflammatory disorders

Abstract

A method for preventing or treating inflammasome-mediated inflammatory disorders, which includes administration of an effective amount of cembrane-type diterpene compound to a subject in need thereof or a subject suffering from inflammation mediated by inflammasome, the cembrane-type diterpene is isolated from soft coral Sinularia flexibilis or Sinularia manaarensis , and the cembrane-type diterpene is cembranolide.

Inventors

• Tsong-Long Hwang
• Jyh-Horng Sheu
• Yu-Chia Chang
• I-Ying Liu
• Yu-Li Chen

Assignees

• CHANG GUNG UNIVERSITY OF SCIENCE AND TECHNOLOGY

Dates

Publication Date

20260507

Application Date

20251029

Claims (10)

1. 1 . A method for preventing or treating inflammasome-mediated inflammatory disorders, comprising administration of a cembrane-type diterpene compound to a subject in need thereof or to a subject suffering from inflammation mediated by inflammasome.
2. 2 . The method of claim 1 , wherein the cembrane-type diterpene compound is cembranolide.
3. 3 . The method of claim 2 , wherein the cembranolide comprises dehydrosinulariolide, dihydroaustrasulfone alcohol, dihydrosinularin, 5-epi-sinuleptolide, 11-epi-sinulariolide acetate, sinularin, sinulariolide or sinuleptolide.
4. 4 . The method of claim 3 , wherein the cembranolide is sinularin.
5. 5 . The method of claim 1 , wherein an effective amount of the cembrane-type diterpene compound is 0.4 mg/kg·bw to 6.1 mg/kg·bw in a 60 kg-weight human.
6. 6 . The method of claim 1 , wherein an effective amount of the cembrane-type diterpene compound is 0.4 mg/kg·bw to 0.8 mg/kg·bw in a 60 kg-weight human by injection.
7. 7 . The method of claim 1 , wherein an effective amount of the cembrane-type diterpene compound is 2 mg/kg to 4.1 mg/kg in a 60 kg-weight human by topical use.
8. 8 . The method of claim 1 , wherein the inflammasome-mediated inflammatory disorders comprise stroke, type II diabetes (T2DM), atherosclerosis, severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), inflammatory bowel disease, atopic dermatitis, psoriasis, alopecia areata, systemic lupus erythematosus (SLE), SLE-induced lupus nephritis (LN), gouty arthritis, rheumatic disease, human autoimmune skin disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, or cryopyrin-associated periodic syndrome (CAPS).
9. 9 . The method of claim 8 , wherein the cryopyrin-associated periodic syndrome (CAPS) comprises familial cold autoinflammatory syndrome (FCAS), Muckle-Well syndrome (MWS), or chronic infantile neurological cutaneous articular syndrome (CINCA).
10. 10 . The method of claim 1 , wherein the subject is human or non-human mammal.

Description

CROSS REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Patent Application No. 63/714,862 filed on Nov. 1, 2024, which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION The present invention relates to a method for preventing or treating inflammasome mediated inflammatory disorders in a subject, particularly, a method for preventing or treating inflammasome mediated inflammatory disorders in a subject by administering cembranolide compounds including dehydrosinulariolide, dihydroaustrasulfone alcohol, dihydrosinularin, 5-epi-Sinuleptolide, 11-epi-Sinulariolide acetate, sinularin, sinulariolide, or sinuleptolide. BACKGROUND OF THE INVENTION Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex composed of apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, when the cells are stimulated to start the activation of NLRP3 inflammasomes, NLRP3, ASC and pro-caspase-1 undergo oligomerization, and ASC will condense to form ASC specks, initiate pro-caspase-1 self-cleavage to produce activated caspase-1, which in turn promotes the maturation of inflammatory factors and triggers a special type of lytic programmed cell death. It is called pyroptosis. The expression and function of NLRP3 inflammasomes are regulated by two steps: priming step (signal I) and activation step (signal II). Priming step (signal I) provides the substances needed by NLRP3 inflammasomes. During the priming step (signal I), macrophage membrane surface receptors recognize pathogen-associated molecular patterns (PAMPs) released from infected or damaged cells, activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and promote the transcription and translation of NLRP3 inflammasome-associated proteins. Lipopolysaccharides (LPS) on the surface of bacteria are common PAMPs, which activate NF-κB through Toll-like receptor-4 (TLR4) and increase the expression of NLRP3, pro IL-1β and pro IL-18 proteins in cells. In the activation step of NLRP3 inflammasomes, many substances are known to act as NLRP3 inflammasome activators to generate activated NLRP3 inflammasomes through different pathways in cells. Adenosine triphosphate (ATP), monosodium urate (MSU), imiquimod (IMQ) and nigericin are common NLRP3 inflammasome activators, which can cause intracellular potassium ion outflow, reactive oxygen species (reactive oxygen species; ROS) generation and lysosomal rupture, which activates NLRP3 inflammasomes and causes pro-caspase-1 to self-cleavage and release caspase-1. Natural compounds are advantageous for their abundant supplies and diverse skeletons, and they are important bases for drug development. From 1981 till 2019, nearly half of the new FDA-approved drugs were derived from natural products or their derivatives, for example, cocaine-derived narcotics, morphine-derived analgesics, vincristine, doxorubicin and paclitaxel for treating cancers, and fungus-derived penicillin as antibiotics. Therefore, the present invention actively investigates which natural compounds have the effect of inhibiting NLRP3 inflammasomes and the potential to be further developed into novel drugs for the treatment or prevention of inflammasome-mediated inflammatory diseases. SUMMARY OF THE INVENTION The present invention is related to a method for preventing or treating inflammasome-mediated inflammatory disorders, which comprises administration of a cembrane-type diterpene compound to a subject in need thereof or to a subject suffering from inflammation mediated by inflammasome. In a preferred manner, the said cembrane-type diterpene is cembranolide. In a most preferred manner, the said cembranolide comprises dehydrosinulariolide, dihydroaustrasulfone alcohol, dihydrosinularin, 5-epi-sinuleptolide, 11-epi-sinulariolide acetate, sinularin, sinulariolide or sinuleptolide. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG. 1 shows the screening results of NLRP3 inflammasome inhibitors, wherein the NLRP3 inflammasome inhibitors are cembrane-type diterpene compounds. Symbol description: “+” refers to receive treatment, “−” refers to not receive treatment, ** refers to statistically significant compared with the nigericin activation alone group (p<0.01); *** refers to statistically significant compared to the nigericin activation alone group (p<0.001). FIG. 2 shows the chemical formula of sinularin. FIG. 3A and FIG. 3B show the cytotoxicity test results for sinularin. LPS means lipopolysaccharide. The results are presented as mean±standard error (n=6 to 8). Symbol description: “+” refers to receive treatment, “−” refers to not receive treatment. FIG. 4 shows the