Chemistry:Trodusquemine

From HandWiki

Trodusquemine is an aminosterol (polyamine steroid conjugate) that inhibits protein tyrosine phosphatase 1B (PTP1B) activity.[1] The compound exhibits broad-spectrum antimicrobial activity[2] and numerous regenerative, neuroprotective, anti-atherosclerotic, antitumor, antiangiogenic, antiobesity, and anxiolytic properties.[3] Phase I clinical trials of trodusquemine have demonstrated good tolerability, but several planned phase II trials were halted due to financial difficulties of the developer.[4]

Chemistry

Trodusquemine is a spermine metabolite of cholesterol. The steroid ring consists of a cholestane with a hydroxyl group at C-7 and sulfate group at C-24; spermine is conjugated to the steroid moiety at C-3. It is structurally similar to squalamine, which features a spermidine moiety instead of spermine.[3]

Pharmacology

Trodusquemine is a non-competitive allosteric inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 1 μmol/L.[5] Inhibition of PTP1B prevents dephosphorylation of the insulin receptor, thereby increasing insulin signaling and lowering blood glucose.[4] Trodusquemine also demonstrates affinity for the dopamine transporter (IC50 0.4 μmol/L) and norepinephrine transporter (IC50 0.7 μmol/L).[5]

Trodusquemine suppresses appetite, promotes weight loss, and rescues hyperglycemia in genetic mouse models of obesity (ob/ob) and diabetes (db/db).[6] Other effects of trodusquemine include amelioration of the metabolic syndrome in mouse models of insulin resistance;[7] correction of hepatic steatosis in ob/ob mice;[8] reversal of atherosclerosis in LDLR knock-out mice;[9] inhibition of the growth of malignancy in rodents;[10] stimulation of the regeneration of tail-fin and heart muscle in zebrafish;[11] stimulation of regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice;[11] prevention of aortic valve calcification in a mouse atheroma model;[12] stimulation of T-cell anti-tumor immunity in a mouse model;[10] correction of systemic and hepatic inflammation, insulin resistance and hepatic dysfunction in horses suffering from equine metabolic syndrome.[13]

Demonstrations of trodusquemine's neuroprotective effects include reversal of memory impairment, normalization of behavior, reduction of neuronal loss and increase in healthspan and lifespan in mouse models of Alzheimer's disease;[14] reduction in alpha-synuclein aggregation and increase in healthspan and lifespan in a C.elegans model of Parkinson's disease;[15] Trodusquemine may exert its effects by targeting specific centers in the brain.[7] Trodusquemine may also have anxiolytic properties.[16]

Although the physiological basis for the healthy lifespan of certain shark species remains unknown, trodusquemine targets well-recognized aging associated processes at both the cellular level and in vivo across many species. These observations conducted in different laboratories suggest that Trodusquemine represents a novel endogenous vertebrate geroprotector.[3]

History

Trodusquemine was originally isolated from liver extracts of the spiny dogfish (Squalus acanthias).[2] It was discovered through a search for antimicrobial compounds in Squaliformes, which lack a robust adaptive immune system. It was hypothesized that their innate immunity might be conferred by endogenous production of antimicrobial compounds.[3]

References

  1. ↑ "Molecule of the Week: Trodusquemine". American Chemical Society. 13 April 2015. https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/trodusquemine.html. 
  2. ↑ 2.0 2.1 "Aminosterols from the dogfish shark Squalus acanthias". Journal of Natural Products 63 (5): 631–5. May 2000. doi:10.1021/np990514f. PMID 10843574. Bibcode: 2000JNAtP..63..631R. 
  3. ↑ 3.0 3.1 3.2 3.3 "Squalamine and trodusquemine: two natural products for neurodegenerative diseases, from physical chemistry to the clinic". Natural Product Reports 39 (4): 742–753. April 2022. doi:10.1039/d1np00042j. PMID 34698757. 
  4. ↑ 4.0 4.1 "From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues". International Journal of Molecular Sciences 23 (3): 1075. January 2022. doi:10.3390/ijms23031075. PMID 35162998. 
  5. ↑ 5.0 5.1 "Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice". Obesity (Silver Spring) 18 (8): 1516–23. August 2010. doi:10.1038/oby.2009.444. PMID 20075852. 
  6. ↑ "A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties". International Journal of Obesity and Related Metabolic Disorders 25 (5): 689–97. May 2001. doi:10.1038/sj.ijo.0801599. PMID 11360152. 
  7. ↑ 7.0 7.1 "Appetite suppression and weight reduction by a centrally active aminosterol". Diabetes 51 (7): 2099–104. July 2002. doi:10.2337/diabetes.51.7.2099. PMID 12086938. 
  8. ↑ "A novel aminosterol reverses diabetes and fatty liver disease in obese mice". Journal of Hepatology 41 (3): 391–8. September 2004. doi:10.1016/j.jhep.2004.05.006. PMID 15336441. 
  9. ↑ "Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis". Clinical Science 131 (20): 2489–2501. October 2017. doi:10.1042/CS20171066. PMID 28899902. 
  10. ↑ 10.0 10.1 "PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity". Cancer Discovery 12 (3): 752–773. March 2022. doi:10.1158/2159-8290.CD-21-0694. PMID 34794959. 
  11. ↑ 11.0 11.1 "The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues". npj Regenerative Medicine 2. 2017. doi:10.1038/s41536-017-0008-1. PMID 29302341. 
  12. ↑ "PTP1B Inhibition Improves Mitochondrial Dynamics to Alleviate Calcific Aortic Valve Disease Via Regulating OPA1 Homeostasis". JACC. Basic to Translational Science 7 (7): 697–712. July 2022. doi:10.1016/j.jacbts.2022.03.002. PMID 35958694. 
  13. ↑ "The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses". Frontiers in Endocrinology 14. 2023. doi:10.3389/fendo.2023.1149610. PMID 37020593. 
  14. ↑ "Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid β-Associated Alzheimer's Disease in Mice". The Journal of Neuroscience 40 (7): 1581–1593. February 2020. doi:10.1523/JNEUROSCI.2120-19.2019. PMID 31915254. 
  15. ↑ "Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine". ACS Chemical Biology 13 (8): 2308–2319. August 2018. doi:10.1021/acschembio.8b00466. PMID 29953201. 
  16. ↑ Torrice, Michael (6 March 2015). "Helping Brains Relieve Anxiety". Chemical & Engineering News 93 (10). https://cen.acs.org/articles/93/i10/Helping-Brains-Relieve-Anxiety.html. Retrieved 30 May 2024. 



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