Squalamine was discovered in a search for anti-microbial compounds in the tissues of primitive vertebrates.[1] The team speculated that animals with primitive immune systems, such as sharks and lampreys, might utilize antimicrobial compounds as a significant component of their immune repertoire. The dogfish shark (Squalus acanthias) was the first shark species studied since it was accessible for research purposes at the Mount Desert Marine Biological Laboratory. In addition, large numbers of dogfish are harvested annually for consumption [2] and could provide sufficient tissue for extraction during the early stages of compound isolation and characterization. The chemical synthesis was developed by William A. Kinney and colleagues,.[3][4]
Squalamine consists of a spermidine coupled to a C-27 sulfated bile salt, a natural product with an unprecedented chemical structure.[5] In addition 7 additional aminosterols were isolated from dogfish liver, including Trodusquemine.[6] Squalamine was later identified in the white blood cells of the lamprey.[7] Squalamine has broad spectrum microbicidal activity,[8][9][10] and its use as a therapeutic has been studied preclinically.[11] In the late 1990’s squalamine was discovered to exhibit antiangiogenic activity,[12][13] and as a consequence was later studied in several early stage clinical trials for both cancer,[14][15][16] age related macular degeneration, administered intravenously,[17][18] and as an eye-drop in combination with intraocular ranibizumab.[19]
In aqueous solution at physiological pH squalamine exists as an amphipathic zwitterion with a net cationic charge. As a consequence the molecule is attracted by electrostatic forces to membranes that display negatively charged phospholipid headgroups, such as the intracellular membranes of animal cells. Once squalamine crosses the plasma membrane of an animal cell it binds to the cytoplasmic surface of the plasma membrane and displaces proteins that are bound electrostatically, a property that explains its inhibition of the sodium-hydrogen transporter type 3,[20] neuronal synaptic AMPA receptors [21] and its broad spectrum antiviral activity.[22]
In 2017, Perni et al reported that squalamine could displace alpha-synuclein from neuronal membranes both in vitro, in isolated cells, and in a C. elegans Parkinson disease model.[23] Since alpha synuclein accumulates within the enteric, peripheral and central nervous system of individuals suffering from Parkinson’s disease where it forms toxic aggregates damaging or killing neurons,[24] squalamine emerged as a potential therapeutic. Studies in mouse models of Parkinson’s disease demonstrated that orally administered squalamine could restore the electrical activity of enteric neurons and thereby restore peristaltic activity, reversing constipation, a non-motor symptom of Parkinson’s disease.[25] Squalamine also restored electrical signaling between the enteric nervous system and the brain ( the “gut-brain axis”).[26] In addition the electrical signals induced by orally administered squalamine phenocopied those elicited by SSRI anti-depressant drugs suggesting that the compound could, via the gut-brain axis, elicit an anti-depressant effect.[27] Based on these preclinical studies squalamine (as the phosphate salt (ENT-01)) was evaluated for the treatment of Parkinson’s disease associated constipation in two clinical trials: RASMET, an open label Phase 1b trial,[28] and subsequently, KARMET, a Phase 2a placebo controlled randomized double blinded trial involving about 150 patients.[29] Both trials, conducted by Enterin, Inc (Philadelphia) demonstrated that a 28 day course of orally administered ENT-03 effectively corrected constipation that had been previously intractable. In addition, positive efficacy signals were seen in circadian rhythm and sleep, dementia and hallucinations. ENT-01 is now (2024) positioned for Phase 3 clinical trials.
squalamine, confused, with, squalene, discovered, search, anti, microbial, compounds, tissues, primitive, vertebrates, team, speculated, that, animals, with, primitive, immune, systems, such, sharks, lampreys, might, utilize, antimicrobial, compounds, signific. Not to be confused with squalene Squalamine was discovered in a search for anti microbial compounds in the tissues of primitive vertebrates 1 The team speculated that animals with primitive immune systems such as sharks and lampreys might utilize antimicrobial compounds as a significant component of their immune repertoire The dogfish shark Squalus acanthias was the first shark species studied since it was accessible for research purposes at the Mount Desert Marine Biological Laboratory In addition large numbers of dogfish are harvested annually for consumption 2 and could provide sufficient tissue for extraction during the early stages of compound isolation and characterization The chemical synthesis was developed by William A Kinney and colleagues 3 4 Squalamine Names IUPAC name 24R 3b 3 3 Aminopropyl amino propyl amino 7a hydroxycholestan 24 yl hydrogen sulfate Systematic IUPAC name 3R 6R 6 1R 3aS 3bR 4R 5aR 7S 9aS 9bS 11aR 7 3 3 Aminopropyl amino propyl amino 4 hydroxy 9a 11a dimethylhexadecahydro 1H cyclopenta a phenanthren 1 yl 2 methylheptan 3 yl hydrogen sulfate Identifiers CAS Number 148717 90 2 3D model JSmol Interactive image ChEMBL ChEMBL444929ChEMBL507931 ChemSpider 65407 KEGG C16841 PubChem CID 72495 UNII F8PO54Z4V7 Y CompTox Dashboard EPA DTXSID40869971 InChI InChI 1S C34H65N3O5S c1 23 2 31 42 43 39 40 41 12 9 24 3 27 10 11 28 32 29 14 16 34 27 28 5 33 4 15 13 26 21 25 33 22 30 32 38 37 20 8 19 36 18 7 6 17 35 h23 32 36 38H 6 22 35H2 1 5H3 H 39 40 41 t24 25 26 27 28 29 30 31 32 33 34 m1 s1Key UIRKNQLZZXALBI MSVGPLKSSA NInChI 1 C34H65N3O5S c1 23 2 31 42 43 39 40 41 12 9 24 3 27 10 11 28 32 29 14 16 34 27 28 5 33 4 15 13 26 21 25 33 22 30 32 38 37 20 8 19 36 18 7 6 17 35 h23 32 36 38H 6 22 35H2 1 5H3 H 39 40 41 t24 25 26 27 28 29 30 31 32 33 34 m1 s1Key UIRKNQLZZXALBI MSVGPLKSBB SMILES CC C C H CC C H C C H 1CC C H 2 C H 3 C H O C C H 4C C H CC C 4 C C H 3CC C 12C NCCCNCCCCN OS O O O Properties Chemical formula C 34H 65N 3O 5S Molar mass 628 g mol Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Infobox references Squalamine consists of a spermidine coupled to a C 27 sulfated bile salt a natural product with an unprecedented chemical structure 5 In addition 7 additional aminosterols were isolated from dogfish liver including Trodusquemine 6 Squalamine was later identified in the white blood cells of the lamprey 7 Squalamine has broad spectrum microbicidal activity 8 9 10 and its use as a therapeutic has been studied preclinically 11 In the late 1990 s squalamine was discovered to exhibit antiangiogenic activity 12 13 and as a consequence was later studied in several early stage clinical trials for both cancer 14 15 16 age related macular degeneration administered intravenously 17 18 and as an eye drop in combination with intraocular ranibizumab 19 In aqueous solution at physiological pH squalamine exists as an amphipathic zwitterion with a net cationic charge As a consequence the molecule is attracted by electrostatic forces to membranes that display negatively charged phospholipid headgroups such as the intracellular membranes of animal cells Once squalamine crosses the plasma membrane of an animal cell it binds to the cytoplasmic surface of the plasma membrane and displaces proteins that are bound electrostatically a property that explains its inhibition of the sodium hydrogen transporter type 3 20 neuronal synaptic AMPA receptors 21 and its broad spectrum antiviral activity 22 In 2017 Perni et al reported that squalamine could displace alpha synuclein from neuronal membranes both in vitro in isolated cells and in a C elegans Parkinson disease model 23 Since alpha synuclein accumulates within the enteric peripheral and central nervous system of individuals suffering from Parkinson s disease where it forms toxic aggregates damaging or killing neurons 24 squalamine emerged as a potential therapeutic Studies in mouse models of Parkinson s disease demonstrated that orally administered squalamine could restore the electrical activity of enteric neurons and thereby restore peristaltic activity reversing constipation a non motor symptom of Parkinson s disease 25 Squalamine also restored electrical signaling between the enteric nervous system and the brain the gut brain axis 26 In addition the electrical signals induced by orally administered squalamine phenocopied those elicited by SSRI anti depressant drugs suggesting that the compound could via the gut brain axis elicit an anti depressant effect 27 Based on these preclinical studies squalamine as the phosphate salt ENT 01 was evaluated for the treatment of Parkinson s disease associated constipation in two clinical trials RASMET an open label Phase 1b trial 28 and subsequently KARMET a Phase 2a placebo controlled randomized double blinded trial involving about 150 patients 29 Both trials conducted by Enterin Inc Philadelphia demonstrated that a 28 day course of orally administered ENT 03 effectively corrected constipation that had been previously intractable In addition positive efficacy signals were seen in circadian rhythm and sleep dementia and hallucinations ENT 01 is now 2024 positioned for Phase 3 clinical trials References edit doi 10 1073 pnas 90 4 1354 Squalus acanthias Convention on the conservation of migratory species of wild animals 2008 doi 10 1021 jo981344z doi 10 1016 S0040 4039 99 00896 5 doi 10 1073 pnas 90 4 1354 doi 10 1021 np990514f doi 10 1194 jlr M700294 JLR200 PMID 23735598 PMID 18648511 PMID 22998181 doi 10 1093 jac dks230 PMID 9661892 PMID 15128931 PMID 11751482 PMID 11751482 PMID 12855619 doi 10 1586 17469899 2 2 165 A Phase I II Trial of Intravenous Squalamine Lactate for Treatment of Choroidal Neovascularization in Age Related Macular Degeneration ARMD https www hcplive com view jason slakter md squalamine lactate eye drops in wet amd doi 10 1038 emboj 2010 356 doi 10 1016 j neuron 2010 04 035 doi org 10 1073 pnas 1108558108 doi 10 1073 pnas 1610586114 Epub 2017 Jan 17 doi 10 1007 s00702 002 0808 2 doi 10 3233 JPD 202076 doi 10 3233 JPD 202076 doi 10 1038 s41598 021 00615 w doi 10 1016 j prdoa 2019 06 001 doi 10 7326 M22 1438 Epub 2022 Nov 8 Retrieved from https en wikipedia org w index php title Squalamine amp oldid 1223211465, wikipedia, wiki, book, books, library,
