RI-AG03 acetate is a proteolytically stable tau aggregation inhibitor that crosses the blood-brain barrier and exhibits oral efficacy. RI-AG03 acetate inhibits tau aggregation and promotes the formation of alternative amorphous aggregates that are non-amyloidogenic. RI-AG03 acetate mediates cellular uptake through direct membrane penetration and macropinocytosis, and its conjugation with cell-penetrating peptide sequences (CPPs) enhances the binding of cells to liposomes. RI-AG03 acetate suppresses aggregation-dependent neurodegenerative and behavioral phenotypes, and extends the lifespan of Drosophila models of tauopathy. RI-AG03 acetate can be used for research on tau-related diseases such as Alzheimer's disease [1] [2] [3].
In Vivo, RI-AG03 (0.08-40 µM; p.o.; continuous dosing; throughout the lifespan or for 6 weeks) acetate reduces Tau aggregation in Drosophila melanogaster, rescues aggregation-dependent neurodegenerative eye phenotypes, and increases the median survival rate of flies expressing hTau2N4R by up to 35% at the dose of 0.8 µM[3].
In Vitro, Liposomes conjugated with RI-AG03 (75 μM; 4 h) acetate show significantly enhanced binding to SH-SY5Y cells[2]. RI-AG03 (20 µM; 24 h) acetate potently inhibits the aggregation of recombinant 306VQIVYK311, 275VQIINK280, and the mixed 306VQIVYK311 + 275VQIINK280 hexapeptides[3]. RI-AG03 (0.5-200 µM; 24 h) acetate dose-dependently inhibits heparin-induced aggregation of recombinant TauΔ1-250, with an IC50 of 7.83 µM[3]. RI-AG03 (0.5-200 µM; 216 h) acetate inhibits heparin-induced aggregation of recombinant full-length Tau2N4R in a dose-dependent manner, with an IC50 of 5 µM[3]. RI-AG03 (20 µM; 24 h) acetate inhibits the formation of recombinant TauΔ1-250 fibrils and instead promotes the formation of large spherical amorphous aggregates[3]. RI-AG03 (20 µM; 5 h) acetate reduces the conversion of recombinant TauΔ1-250 from a disordered random coil structure to β-sheet-rich aggregates[3]. RI-AG03 (0.5-500 µM; 16 h preincubation, 24 h cell incubation) acetate ose-dependently inhibits the seeding aggregation of preformed Tau2N4R fibrils in HEK-293 Tau biosensor cells, with an IC50 of 23.85 µM, and shows no toxicity at effective doses up to 100 µM[3].
References:
[1]. Di Natale G, et al. Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer's Disease? Molecules. 2022 Aug 9;27(16):5066.
[2]. Reich N, et al. Liposome nanoparticle conjugation and cell penetrating peptide sequences (CPPs) enhance the cellular delivery of the tau aggregation inhibitor RI-AG03. J Cell Mol Med. 2024;28(11):e18477.
[3]. Aggidis A, et al. A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies. Alzheimers Dement. 2024 Nov;20(11):7788-7804.
In Vivo, RI-AG03 (0.08-40 µM; p.o.; continuous dosing; throughout the lifespan or for 6 weeks) acetate reduces Tau aggregation in Drosophila melanogaster, rescues aggregation-dependent neurodegenerative eye phenotypes, and increases the median survival rate of flies expressing hTau2N4R by up to 35% at the dose of 0.8 µM[3].
In Vitro, Liposomes conjugated with RI-AG03 (75 μM; 4 h) acetate show significantly enhanced binding to SH-SY5Y cells[2]. RI-AG03 (20 µM; 24 h) acetate potently inhibits the aggregation of recombinant 306VQIVYK311, 275VQIINK280, and the mixed 306VQIVYK311 + 275VQIINK280 hexapeptides[3]. RI-AG03 (0.5-200 µM; 24 h) acetate dose-dependently inhibits heparin-induced aggregation of recombinant TauΔ1-250, with an IC50 of 7.83 µM[3]. RI-AG03 (0.5-200 µM; 216 h) acetate inhibits heparin-induced aggregation of recombinant full-length Tau2N4R in a dose-dependent manner, with an IC50 of 5 µM[3]. RI-AG03 (20 µM; 24 h) acetate inhibits the formation of recombinant TauΔ1-250 fibrils and instead promotes the formation of large spherical amorphous aggregates[3]. RI-AG03 (20 µM; 5 h) acetate reduces the conversion of recombinant TauΔ1-250 from a disordered random coil structure to β-sheet-rich aggregates[3]. RI-AG03 (0.5-500 µM; 16 h preincubation, 24 h cell incubation) acetate ose-dependently inhibits the seeding aggregation of preformed Tau2N4R fibrils in HEK-293 Tau biosensor cells, with an IC50 of 23.85 µM, and shows no toxicity at effective doses up to 100 µM[3].
References:
[1]. Di Natale G, et al. Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer's Disease? Molecules. 2022 Aug 9;27(16):5066.
[2]. Reich N, et al. Liposome nanoparticle conjugation and cell penetrating peptide sequences (CPPs) enhance the cellular delivery of the tau aggregation inhibitor RI-AG03. J Cell Mol Med. 2024;28(11):e18477.
[3]. Aggidis A, et al. A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies. Alzheimers Dement. 2024 Nov;20(11):7788-7804.