Chemistry:Celastrol

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Celastrol (tripterine) is a bioactive chemical compound isolated from the roots of Tripterygium wilfordii (Thunder duke vine) and Tripterygium regelii (Regel's threewingnut). Celastrol is a pentacyclic nortriterpen quinone and belongs to the family of quinone methides.[1] It has been used for centuries as a traditional Chinese medicine. In recent years, celastrol has been widely studied for its anti-inflammatory, anticancer, antioxidant, and antibacterial properties.[2][3][4][5]

In mice, celastrol is an NR4A1 agonist that alleviates inflammation and induces autophagy.[6] It also influences metabolic regulation by enhancing IL1R1 expression, which is the receptor for the cytokine interleukin-1 (IL-1). IL1R1 knock-out mice exposed to celastrol exhibit no leptin-sensitizing or anti-obesity effect.[7]

In in vitro and in vivo animal experiments, celastrol exhibits antibacterial,[8][5] antioxidant,[9] anti-inflammatory,[10][11] anticancer,[12][13][14][15][16] and insecticidal properties.[17] It has been shown to have obesity-controlling effects in mice by inhibiting negative regulators of leptin.[18][19][20] Celastrol has also shown to possess anti-diabetic effects on diabetic nephropathy and improve whole-body insulin resistance, through the inhibition of NF-κB signaling in the hypothalamus.[21]

Celastrol inhibits the IKK-NF-κB signaling pathway via multiple molecular mechanisms, including the direct inhibition of IKKα and IKKβ kinases, inactivation of CDC37 and p23 (HSP90 chaperone proteins), suppression of proteasome function and activation of HSF1, which triggers the heat shock response. The available evidence indicates that celastrol covalently binds to the thiol groups of cysteine residues within its molecular targets.[22]

Celastrol also has demonstrated in vitro inhibitory effects against the carbapenemase of carbapenem-resistant Klebsiella pneumoniae (CRE), particularly when used in combination with thymol, a monoterpene.[23]

Antibacterial activity against MRSA

Recent studies have identified celastrol as a potential antibacterial agent against methicillin-resistant Staphylococcus aureus (MRSA). Multi-omics analysis suggests that celastrol targets bacterial Δ¹-pyrroline-5-carboxylate dehydrogenase (P5CDH), which is an enzyme involved in proline metabolism. Molecular docking identified Lys205 and Glu208 as critical binding sites for celastrol on P5CDH.[5]

By binding to P5CDH, celastrol disrupts its function and leads to an accumulation of Δ1-pyrroline-5-carboxylate (P5C). This disruption interferes with bacterial oxidative stress regulation, resulting in an increase in reactive oxygen species (ROS) and oxidative damage. Additionally, the inhibition of P5CDH disrupts bacterial energy production and DNA synthesis, ultimately leading to bacterial cell death. Because celastrol affects multiple bacterial metabolic pathways, it is a promising candidate for drug development.[5]

Experiments in vitro demonstrated that celastrol exhibits significant antibacterial activity against Gram-positive bacteria, including multiple MRSA strains. However, it is significantly less effective against Gram-negative bacteria due to structural differences in their cell wall structures. The compound also demonstrated low levels of resistance development compared to traditional antibiotics such as vancomycin and oxacillin.[5]

In vivo studies using Galleria mellonella larvae and murine infection models showed that celastrol effectively reduced bacterial burden and improved survival rates in MRSA-infected animals. However, high doses of celastrol led to toxicity, including hepatotoxicity and renal damage. Additionally, celastrol's therapeutic window is narrow, meaning that only a specific dosage range is effective. It was also shown that in high concentrations, celastrol induces apoptosis in spleen cells. These findings suggest that celastrol may not be suitable for direct clinical use. On the other hand, celastrol should be used as a lead compound for developing safer and more effective derivatives.[5]

References

  1. ↑ "Celastrol: The new dawn in the treatment of vascular remodeling diseases". Biomedicine & Pharmacotherapy 158. February 2023. doi:10.1016/j.biopha.2022.114177. PMID 36809293. 
  2. ↑ "The role of celastrol in inflammation and diseases". Inflammation Research 74 (1): 23. January 2025. doi:10.1007/s00011-024-01983-5. PMID 39862265. 
  3. ↑ "Molecular targets of celastrol in cancer: Recent trends and advancements". Critical Reviews in Oncology/Hematology 128: 70–81. August 2018. doi:10.1016/j.critrevonc.2018.05.019. PMID 29958633. 
  4. ↑ "Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1". Signal Transduction and Targeted Therapy 8 (1): 51. February 2023. doi:10.1038/s41392-022-01231-4. PMID 36732502. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Celastrol Combats Methicillin-Resistant Staphylococcus aureus by Targeting Δ1 -Pyrroline-5-Carboxylate Dehydrogenase". Advanced Science 10 (25). September 2023. doi:10.1002/advs.202302459. PMID 37381655. 
  6. ↑ "The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases". Journal of Diabetes Research 2018. 2018. doi:10.1155/2018/9363461. PMID 30013988. 
  7. ↑ "IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects". Nature Medicine 25 (4): 575–582. April 2019. doi:10.1038/s41591-019-0358-x. PMID 30833749. 
  8. ↑ "Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources". Foods 10 (3): 591. March 2021. doi:10.3390/foods10030591. PMID 33799720. 
  9. ↑ "Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease". Progress in Neuro-Psychopharmacology & Biological Psychiatry 25 (7): 1341–57. October 2001. doi:10.1016/S0278-5846(01)00192-0. PMID 11513350. 
  10. ↑ "Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii". European Journal of Clinical Investigation 39 (9): 819–27. September 2009. doi:10.1111/j.1365-2362.2009.02186.x. PMID 19549173. 
  11. ↑ "Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses". The Journal of Biological Chemistry 286 (17): 15138–46. April 2011. doi:10.1074/jbc.M111.226365. PMID 21402700. 
  12. ↑ "Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin". eBioMedicine 50: 81–92. November 2019. doi:10.1016/j.ebiom.2019.10.062. PMID 31735550. 
  13. ↑ "Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90". International Journal of Molecular Medicine 27 (3): 441–6. March 2011. doi:10.3892/ijmm.2011.601. PMID 21249311. 
  14. ↑ "Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo". Blood 113 (17): 4027–37. April 2009. doi:10.1182/blood-2008-09-179796. PMID 19096011. 
  15. ↑ "Celastrol acts as a potent antimetastatic agent targeting beta1 integrin and inhibiting cell-extracellular matrix adhesion, in part via the p38 mitogen-activated protein kinase pathway". The Journal of Pharmacology and Experimental Therapeutics 334 (2): 489–99. August 2010. doi:10.1124/jpet.110.165654. PMID 20472666. 
  16. ↑ "Reactive oxygen species-dependent activation of Bax and poly(ADP-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid pristimerin in human cervical cancer cells". Molecular Pharmacology 76 (4): 734–44. October 2009. doi:10.1124/mol.109.056259. PMID 19574249. 
  17. ↑ "Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone methides against codling moth, Cydia pomonella (L.) (Lepidoptera: tortricidae)". Journal of Agricultural and Food Chemistry 48 (1): 88–92. January 2000. doi:10.1021/jf990008w. PMID 10637057. Bibcode: 2000JAFC...48...88A. 
  18. ↑ Kyriakou E, Schmidt S, Dodd GT, et al. Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. J Med Chem. 2018;61(24):11144-11157. doi:10.1021/acs.jmedchem.8b01224
  19. ↑ "Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1". Diabetes 67 (11): 2456–2465. November 2018. doi:10.2337/db18-0146. PMID 30158241. 
  20. ↑ "Treatment of obesity with celastrol". Cell 161 (5): 999–1011. May 2015. doi:10.1016/j.cell.2015.05.011. PMID 26000480. 
  21. ↑ "Celastrol, an NF-κB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice". PLOS ONE 8 (4). 2013. doi:10.1371/journal.pone.0062068. PMID 23637966. Bibcode: 2013PLoSO...862068K.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  22. ↑ "Celastrol: Molecular targets of Thunder God Vine". Biochem Biophys Res Commun 394 (3): 439–42. April 2010. doi:10.1016/j.bbrc.2010.03.050. PMID 20226165. 
  23. ↑ "In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates". The Journal of Antibiotics 75 (12): 679–690. 27 September 2022. doi:10.1038/s41429-022-00566-y. PMID 36167781. 



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