Trodusquemine

Trodusquemine
Clinical data
Other namesMSI-1436
ATC code
  • None
Identifiers
  • [(3R,6R)-6-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-[3-[4-(3-Aminopropylamino)butylamino]propylamino]-7-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-yl] hydrogen sulfate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC37H72N4O5S
Molar mass685.07 g·mol−1
3D model (JSmol)
  • C[C@H](CC[C@H](C(C)C)OS(=O)(=O)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@@H](C[C@@H]4[C@@]3(CC[C@@H](C4)NCCCNCCCCNCCCN)C)O)C
  • InChI=1S/C37H72N4O5S/c1-26(2)34(46-47(43,44)45)13-10-27(3)30-11-12-31-35-32(15-17-37(30,31)5)36(4)16-14-29(24-28(36)25-33(35)42)41-23-9-22-40-20-7-6-19-39-21-8-18-38/h26-35,39-42H,6-25,38H2,1-5H3,(H,43,44,45)/t27-,28-,29+,30-,31+,32+,33-,34-,35+,36+,37-/m1/s1
  • Key:WUJVPODXELZABP-FWJXURDUSA-N

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.
  2. ^ a b Rao MN, Shinnar AE, Noecker LA, Chao TL, Feibush B, Snyder B, et al. (May 2000). "Aminosterols from the dogfish shark Squalus acanthias". Journal of Natural Products. 63 (5): 631–5. doi:10.1021/np990514f. PMID 10843574.
  3. ^ a b c d Limbocker R, Errico S, Barbut D, Knowles TP, Vendruscolo M, Chiti F, et al. (April 2022). "Squalamine and trodusquemine: two natural products for neurodegenerative diseases, from physical chemistry to the clinic". Natural Product Reports. 39 (4): 742–753. doi:10.1039/d1np00042j. hdl:2158/1284768. PMID 34698757.
  4. ^ a b Kazakova O, Giniyatullina G, Babkov D, Wimmer Z (January 2022). "From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues". International Journal of Molecular Sciences. 23 (3): 1075. doi:10.3390/ijms23031075. PMC 8834734. PMID 35162998.
  5. ^ a b Lantz KA, Hart SG, Planey SL, Roitman MF, Ruiz-White IA, Wolfe HR, et al. (August 2010). "Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice". Obesity (Silver Spring). 18 (8): 1516–23. doi:10.1038/oby.2009.444. PMID 20075852.
  6. ^ Zasloff M, Williams JI, Chen Q, Anderson M, Maeder T, Holroyd K, et al. (May 2001). "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. doi:10.1038/sj.ijo.0801599. PMID 11360152.
  7. ^ a b Ahima RS, Patel HR, Takahashi N, Qi Y, Hileman SM, Zasloff MA (July 2002). "Appetite suppression and weight reduction by a centrally active aminosterol". Diabetes. 51 (7): 2099–104. doi:10.2337/diabetes.51.7.2099. PMID 12086938.
  8. ^ Takahashi N, Qi Y, Patel HR, Ahima RS (September 2004). "A novel aminosterol reverses diabetes and fatty liver disease in obese mice". Journal of Hepatology. 41 (3): 391–8. doi:10.1016/j.jhep.2004.05.006. PMID 15336441.
  9. ^ Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N, et al. (October 2017). "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. doi:10.1042/CS20171066. PMC 6365594. PMID 28899902.
  10. ^ a b Wiede F, Lu KH, Du X, Zeissig MN, Xu R, Goh PK, et al. (March 2022). "PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity". Cancer Discovery. 12 (3): 752–773. doi:10.1158/2159-8290.CD-21-0694. PMC 8904293. PMID 34794959.
  11. ^ a b Smith AM, Maguire-Nguyen KK, Rando TA, Zasloff MA, Strange KB, Yin VP (2017). "The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues". npj Regenerative Medicine. 2: 4. doi:10.1038/s41536-017-0008-1. PMC 5677970. PMID 29302341.
  12. ^ Liu F, Chen J, Hu W, Gao C, Zeng Z, Cheng S, et al. (July 2022). "PTP1B Inhibition Improves Mitochondrial Dynamics to Alleviate Calcific Aortic Valve Disease Via Regulating OPA1 Homeostasis". JACC. Basic to Translational Science. 7 (7): 697–712. doi:10.1016/j.jacbts.2022.03.002. PMC 9357565. PMID 35958694.
  13. ^ Bourebaba L, Serwotka-Suszczak A, Pielok A, Sikora M, Mularczyk M, Marycz K (2023). "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: 1149610. doi:10.3389/fendo.2023.1149610. PMC 10067883. PMID 37020593.
  14. ^ Ricke KM, Cruz SA, Qin Z, Farrokhi K, Sharmin F, Zhang L, et al. (February 2020). "Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid β-Associated Alzheimer's Disease in Mice". The Journal of Neuroscience. 40 (7): 1581–1593. doi:10.1523/JNEUROSCI.2120-19.2019. PMC 7044730. PMID 31915254.
  15. ^ Perni M, Flagmeier P, Limbocker R, Cascella R, Aprile FA, Galvagnion C, et al. (August 2018). "Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine". ACS Chemical Biology. 13 (8): 2308–2319. doi:10.1021/acschembio.8b00466. hdl:10261/253531. PMID 29953201.
  16. ^ Torrice M (6 March 2015). "Helping Brains Relieve Anxiety". Chemical & Engineering News. 93 (10). Retrieved 30 May 2024.