9-Methylfascaplysin Is a More Potent Aβ Aggregation Inhibitor than the Marine-Derived Alkaloid, Fascaplysin, and Produces Nanomolar Neuroprotective Effects in SH-SY5Y Cells

Abstract

β-Amyloid (Aβ) is regarded as an important pathogenic target for Alzheimer’s disease (AD), the most prevalent neurodegenerative disease. Aβ can assemble into oligomers and fibrils, and produce neurotoxicity. Therefore, Aβ aggregation inhibitors may have anti-AD therapeutic efficacies. It was found, here, that the marine-derived alkaloid, fascaplysin, inhibits Aβ fibrillization in vitro. Moreover, the new analogue, 9-methylfascaplysin, was designed and synthesized from 5-methyltryptamine. Interestingly, 9-methylfascaplysin is a more potent inhibitor of Aβ fibril formation than fascaplysin. Incubation of 9-methylfascaplysin with Aβ directly reduced Aβ oligomer formation. Molecular dynamics simulations revealed that 9-methylfascaplysin might interact with negatively charged residues of Aβ42 with polar binding energy. Hydrogen bonds and π–π interactions between the key amino acid residues of Aβ42 and 9-methylfascaplysin were also suggested. Most importantly, compared with the typical Aβ oligomer, Aβ modified by nanomolar 9-methylfascaplysin produced less neuronal toxicity in SH-SY5Y cells. 9-Methylfascaplysin appears to be one of the most potent marine-derived compounds that produces anti-Aβ neuroprotective effects. Given previous reports that fascaplysin inhibits acetylcholinesterase and induces P-glycoprotein, the current study results suggest that fascaplysin derivatives can be developed as novel anti-AD drugs that possibly act via inhibition of Aβ aggregation along with other target mechanisms.

Benefits under the Sea: The Role of Marine Compounds in Neurodegenerative Disorders

“…One of the most powerful marine-derived compounds that produce in vitro neuroprotective effects is the 9-methylfascaplysin. In the research of Sun et al [ 133 ], fascaplysin was used for designing 9-methylfascaplysin to improve its activity. Fascaplysin ( Figure 7 ) is a extensively active benzoyl-linked β-carboline alkaloid initially extracted from the Fijian sponge Fascaplysinopsis ; this molecule showed antitumoral and antioxidative effects [ 134 ].…”

Dimeric Tacrine (10)-Hupyridone Effectively Combats Alzheimer’s Disease as A Multi-Target-Directed Ligand

“…Aβ oligomer preparation was described in previous studies reported by us [27][28][29]. Brie y, Aβ peptide was dissolved in hexa uoroisopropanol (HFIP, Aladdin, Shanghai, China) to form Aβ monomers.…”

Marine Natural Products, Multitarget Therapy and Repurposed Agents in Alzheimer’s Disease

“…Based on molecular modeling studies, 9-methylfascaplysin ( Figure 5 g), a fascaplysin derivative, was synthesized [ 60 , 61 ]. Docking analyses suggested that the binding to AChE active site differs from fascaplysin, which only binds to the peripheral anionic site.…”

“…9-Methylfascaplysin and Aβ possibly interact through hydrogen bonding and hydrophobic interactions, including π-π interactions. It is thought that the direct interaction between this fascaplysin derivative and Aβ causes competition between the intramolecular bonds of Aβ aggregates leading to the inhibition of Aβ self-assembly [ 61 ]. Studies performed in vitro also showed its potential to activate antioxidant enzymes and thus, to produce neuroprotective effects against ROS.…”