Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors

Visentin, Cristina; Musso, Loana; Broggini, Luca; Bonato, Francesca; Russo, Rosaria; Moriconi, Claudia; Bolognesi, Martino; Miranda, Elena; Dallavalle, Sabrina; Passarella, Daniele; Ricagno, Stéfano

doi:10.3390/life10070111

Cited by 11 publications

(6 citation statements)

References 44 publications

(107 reference statements)

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“…Catalytic (10 %) amounts of manganese acetate dihydrate (MAH) could efficiently promote the addition of n ‐butylamine to CBDQ ( 1 a ) without replacing the enolic hydroxyl with an amine functionality, a known reaction of O ‐alkyl hydroxyquinones, or generating iminoquinones (Scheme 2). [9] MAH could efficiently promote the addition of various primary amines to both CBDQ ( 1 a ) and CBGQ ( 2 a ). Conversely, secondary amines were unreactive, presumably for steric reasons associated to the presence of the adjacent n ‐pentyl group on the quinone core.…”

Section: Resultsmentioning

confidence: 99%

One‐Pot Oxidative Heterofunctionalization of Resorcinolic Cannabinoids to Non‐thiophilic Aminocannabinoquinones

et al. 2022

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Aminocannabinoquinones are an emerging class of next generation semi‐synthetic cannabinoids exemplified by VCE‐004.8 (1 c), a compound currently in phase 2 development for scleroderma. Aminocannabinoquinones have been so far obtained from resorcinolic cannabinoids by a two‐step protocol involving oxidation to a hydroxyquinone followed by tandem aza‐Michael trapping by a primary amine and in situ reoxidation. To improve this synthesis and to broaden its substrate range, we have capitalized on the dual ability of manganese (III) acetate hydrate (MAH) to act as a one‐electron oxidant for electron‐rich aromatics as well as a Lewis acid promoter for Michael addition. This led to the development of a one‐pot protocol for the oxidative heterofunctionalization of cannabinoids to aminocannabinoquinones suitable for the expeditious generation of libraries. Unlike cannabinoquinones, these amino derivatives are not thiophylic, providing a possible rationalization for the different stability and biological profile of the two classes of compounds.

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Section: Resultsmentioning

confidence: 99%

One‐Pot Oxidative Heterofunctionalization of Resorcinolic Cannabinoids to Non‐thiophilic Aminocannabinoquinones

et al. 2022

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“…Embelin, a small molecule derived from the Japanese Ardisia herb, prevented in vitro NS aggregation and dissolve aggregates. 67,68 ABE correction of the pathogenic variant to prevent new aggregation combined with embelin disruption of existing aggregates is a potential effective therapy.…”

Section: Discussionmentioning

confidence: 99%

Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing

Konishi,

Moulayes,

Butola

et al. 2024

Preprint

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Altered protein conformation can cause incurable neurodegenerative disorders. Mutations inSERPINI1, the gene encoding neuroserpin, alter protein conformation resulting in cytotoxic aggregation in neuronal endoplasmic reticulum. Aggregates cause oxidative stress impairing function, leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy. Patients present with seizures and cognitive impairments that progress to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring the patient's pathogenicSERPINI1variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). FENIB cells form neuroserpin inclusions which increase in size and number. Here, we utilized a personalized adenine base editor (ABE)-mediated approach to efficiently correct the pathogenic variant and to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted neuronal impairments. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery. Preventing mutant protein with altered conformation production improved toxic protein clearance. Our findings provide a targeted strategy and may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer's and Huntington's diseases.

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“…2 B, oligomers NS-EMB ) [ 53 ]. Unfortunately, several attempts to ameliorate the solubility of embelin and its affinity for neuroserpin have shown that even minor chemical modifications result in a marked reduction of its antipolymerisation activity [ 65 ].…”

Section: Polymerisation Of Neuroserpinmentioning

confidence: 99%

Neuroserpin: structure, function, physiology and pathology

D'Acunto

Fra

Visentin

et al. 2021

Cell. Mol. Life Sci.

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Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.

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Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors

Cited by 11 publications

References 44 publications

One‐Pot Oxidative Heterofunctionalization of Resorcinolic Cannabinoids to Non‐thiophilic Aminocannabinoquinones

One‐Pot Oxidative Heterofunctionalization of Resorcinolic Cannabinoids to Non‐thiophilic Aminocannabinoquinones

Modeling and Correction of Protein Conformational Disease in iPSC-derived Neurons through Personalized Base Editing

Neuroserpin: structure, function, physiology and pathology

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