claramine / Northwestern University - LARVOL DELTA

An aminosterol breaks the autocatalytic cycle of Aβ42 aggregation and protects cell membranes from its soluble aggregates. (PubMed, Proc Natl Acad Sci U S A) - "Upon exposure of human neuroblastoma cells to stabilized Aβ42 oligomers, claramine effectively neutralized Aβ42 oligomer-induced cytotoxicity by preventing their binding to cell membranes. Owing to the unique mechanism of action of aminosterols to reduce the toxicity of soluble Aβ42 aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit Aβ42 fibril formation and dissociate fibrillar Aβ42 resulting in the interruption of the positive feedback loop in Aβ42 aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases."

Journal • Alzheimer's Disease • CNS Disorders • Neuroblastoma • Oncology • Proteinopathy • Solid Tumor • Aβ42

Pharmacological inhibition of α-synuclein aggregation within liquid condensates. (PubMed, Nat Commun) - "By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Upregulation of PTPN1 aggravates endotoxemia-induced cardiac dysfunction through inhibiting mitophagy. (PubMed, Int Immunopharmacol) - "PTPN1 upregulation aggravates endotoxemia-induced cardiac dysfunction by impeding mitophagy through dephosphorylation of STAT3 at Y705 and negative regulation of PINK1 and PRKN transcription."

Journal • Infectious Disease • Septic Shock • PINK1 • PTPN1

PTP1B Inhibitor Claramine Rescues Diabetes-Induced Spatial Learning and Memory Impairment in Mice. (PubMed, Mol Neurobiol) - "Furthermore, CA treatment not only significantly down-regulated the expressions of PTP1B and NLRP3 inflammatory related proteins (NLRP3, ASC, Caspase-1, COX-2, IL-1β, and TNF-α), but also significantly up-regulated the expressions of insulin signaling pathway-related proteins (p-IRS1, p-PI3K, p-AKT, and p-GSK-3β) in diabetic mice. Taken together, these results suggested that PTP1B might be a targeted strategy to rescue learning and memory deficits in DM, possibly through inhibition of NLRP3 inflammasome and regulation of insulin signaling pathway."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Diabetes • Metabolic Disorders • IL1B • NLRP3 • PTPN1 • TNFA

Hyperinsulinemia alters insulin receptor presentation and internalization in brain microvascular endothelial cells. (PubMed, Diab Vasc Dis Res) - "Claramine restored signaling and receptor internalization in cells treated with hyperinsulinemia. In conclusion, hyperinsulinemia impacts brain microvascular endothelial cell insulin receptor signaling and internalization, likely via alternative splicing and increased negative feedback from PTP1B."

Journal • CNS Disorders • Genetic Disorders • IR • PTPN1

CD36 gene deletion reduces muscle insulin sensitivity in mice by up-regulating PTP1B expression (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "CD36 is essential for maintaining muscle insulin sensitivity under physiological conditions, and CD36 gene deletion in mice causes impaired insulin sensitivity by up-regulating muscle PTP1B expression, which results in detyrosine phosphorylation of IR and IRS1."

Journal • Preclinical • CD36 • IRS1 • IRS2 • PTPN1

A Brain-Permeable Aminosterol Regulates Cell Membranes to Mitigate the Toxicity of Diverse Pore-Forming Agents. (PubMed, ACS Chem Neurosci) - "In this study, we investigate the ability of claramine, a blood-brain barrier permeable small molecule in the aminosterol class, to neutralize the toxicity of acute biological threat agents, including melittin from honeybee venom and α-hemolysin from Staphylococcus aureus...We thus demonstrate that the exogenous administration of an aminosterol can tune the properties of lipid membranes and protect cells from diverse biotoxins, including not just misfolded protein oligomers as previously shown but also biological protein-based toxins. Our results indicate that the investigation of regulators of the physicochemical properties of cell membranes offers novel opportunities to develop countermeasures against an extensive set of cytotoxic effects associated with cell membrane disruption."

Journal

From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues. (PubMed, Int J Mol Sci) - "This review comprehensively describes the recent advances in the synthesis and pharmacological evaluation of steroid polyamines squalamine, trodusquemine, ceragenins, claramine, and their diverse analogs and derivatives, with a special focus on their complete synthesis from cholic acids, as well as an antibacterial and antiviral, neuroprotective, antiangiogenic, antitumor, antiobesity and weight-loss activity, antiatherogenic, regenerative, and anxiolytic properties. The discovery of squalamine as the first representative of a previously unknown class of natural antibiotics of animal origin stimulated extensive research of terpenoids (especially triterpenoids) comprising polyamine fragments. During the last decade, this new class of biologically active semisynthetic natural product derivatives demonstrated the possibility to form supramolecular networks, which opens up many possibilities for the use of such structures for drug delivery systems in serum or other body fluids."

Journal • Review • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Oncology • PTPN1

Indole- and Pyrazole-Glycyrrhetinic Acid Derivatives as PTP1B Inhibitors: Synthesis, In Vitro and In Silico Studies. (PubMed, Molecules) - "The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC = 2.5 µM) than that of positive controls ursolic acid (IC = 5.6 µM), claramine (IC = 13.7 µM) and suramin (IC = 4.1 µM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • LEP • PTPN1

The aminosterol Claramine inhibits β-secretase 1-mediated insulin receptor cleavage. (PubMed, J Biol Chem) - "Both of these effects likely contribute to the reduced amount of the proform of BACE1 in the early secretory pathway, thereby reducing insulin receptor cleavage. These newly described properties of Claramine are consistent with its insulin sensitizing effect."

Journal • Diabetes • Metabolic Disorders • Targeted Protein Degradation • IR