Trodusquemine
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| Other names | MSI-1436 |
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| Formula | C37H72N4O5S |
| Molar mass | 685.07 g·mol−1 |
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Trodusquemine is an aminosterol (a polyamine-steroid) that is an allosteric inhibitor of protein-tyrosine phosphatase 1B (PTP1B).[1]. It was isolated from the liver of the dogfish shark by Michael Zasloff and colleagues in 2000 [2] and underwent three Phase 1 studies as a treatment for diabetes and obesity,[3] and despite safety and signals of efficacy, development was discontinued because it could only be formulated for intravenous use.
Trodusquemine was discovered in a search for antimicrobial compounds supporting the innate immune system.[4] The search was motivated by the hypothesis that the surprising degree of immunity exhibited by certain animals could be due to the presence of endogenous antimicrobial compounds. The dogfish shark fell into that category. Sharks have an adaptive immune system that responds too slowly to defend against most bacterial or viral infections so one might imagine that these animals would be relatively short lived.[5] Surprisingly, the dogfish enjoys a healthy lifespan with an age limit of at least 100 years.[6] In fact, another member of the Squaliformes, the Greenland shark, is the longest living vertebrate with a male life span of at least 392 (+/- 120) years.[7] Trodusquemine has been shown to exert its effects by targeting specific centers in the brain.[8]
The therapeutic effects of Trodusquemine demonstrated in animals include amelioration of the metabolic syndrome in mouse models of insulin resistance;[9] correction of hepatic steatosis in obese (ob/ob) mice;[10] reversal of atherosclerosis in LDLR knock-out mice;[11] inhibition of the growth of malignancy in rodents;[12] stimulation of the regeneration of tail-fin and heart muscle in zebrafish;[13] stimulation of regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice;[14] reversal of memory impairment, normalization of behavior, reduction of neuronal loss and increase in healthspan and lifespan in mouse models of Alzheimer's disease;[15] reduction in alpha-synuclein aggregation and increase in healthspan and lifespan in a C.elegans Parkinson's model;[16] prevention of aortic valve calcification in a mouse atheroma model;[17] stimulation of T-cell anti-tumor immunity in a mouse model;[18] correction of systemic and hepatic inflammation, insulin resistance and hepatic dysfunction in horses suffering from equine metabolic syndrome.[19]
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.
References[edit]
- ^ "Molecule of the Week: Trodusquemine". American Chemical Society. April 13, 2015.
- ^ PMID=11360152
- ^ PMID=34698757
- ^ PMID=34698757
- ^ PMID=15688348
- ^ Squalua Acanthias.Convention on the conservation of migratory species of wild animals 2008
- ^ PMID=27516602
- ^ PMID=12086938
- ^ PMID=12086938
- ^ PMID=15336441
- ^ PMID=28899902
- ^ PMID=34794959
- ^ PMID=29302341
- ^ PMID=29302341
- ^ PMID=31915254
- ^ PMID=29953201
- ^ PMID=35958694
- ^ PMID=34794959
- ^ PMID=37020593