Plant isoquinoline alkaloids as potential neurodrugs: A comparative study of the effects of benzo[c]phenanthridine and berberine-based compounds on β-amyloid aggregation

Marasco, Daniela; Vicidomini, Caterina; Krupa, Paweł; Cioffi, Federica; Huy, Pham Dinh Quoc; Li, Mai Suan; Florio, Daniele; Broersen, Kerensa; Pandis, Maria Francesca De; Roviello, Giovanni N.

doi:10.1016/j.cbi.2020.109300

Cited by 32 publications

(20 citation statements)

References 102 publications

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“…In recent years, naturally derived alkaloids have been involved in the management of neurodegenerative diseases and have shown high potential in inhibiting amyloid aggregation [ 36 , 39 , 48 , 49 ]. Given the importance of seeds in the pathological amyloid formation in vitro and in vivo [ 2 , 50 , 51 , 52 , 53 ], we screened nine Chinese herbal alkaloid compounds for their effect on seeded induced α-syn aggregation.…”

Section: Resultsmentioning

confidence: 99%

Natural Alkaloid Compounds as Inhibitors for Alpha-Synuclein Seeded Fibril Formation and Toxicity

et al. 2021

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The accumulation and aggregation of α-synuclein (α-syn) is the main pathologic event in Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-Syn-seeded fibril formation and its induced toxicity occupy a major role in PD pathogenesis. Thus, assessing compounds that inhibit this seeding process is considered a key towards the therapeutics of synucleinopathies. Using biophysical and biochemical techniques and seeding-dependent cell viability assays, we screened a total of nine natural compounds of alkaloid origin extracted from Chinese medicinal herbs. Of these compounds, synephrine, trigonelline, cytisine, harmine, koumine, peimisine, and hupehenine exhibited in vitro inhibition of α-syn-seeded fibril formation. Furthermore, using cell viability assays, six of these compounds inhibited α-syn-seeding-dependent toxicity. These six potent inhibitors of amyloid fibril formation and toxicity caused by the seeding process represent a promising therapeutic strategy for the treatment of PD and other synucleinopathies.

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Section: Resultsmentioning

confidence: 99%

Natural Alkaloid Compounds as Inhibitors for Alpha-Synuclein Seeded Fibril Formation and Toxicity

et al. 2021

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“…Molecular Docking. In order to carry out the molecular docking studies, we obtained the most representative monomeric model of the protein that were reported by Marasco and co-workers 55 and were based on the extensive computational studies of Krupa and coworkers 56 involving S-shape and U-shape fibril models (PDB codes 2LMN and 2MXU).…”

Section: ■ Experimental Methodsmentioning

confidence: 99%

Structure Dependent Differential Modulation of Aβ Fibrillization by Selenadiazole-Based Inhibitors

Kalsoom

Alazmi

Farrukh

et al. 2021

ACS Chem. Neurosci.

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Misfolding and fibrillar aggregation of Aβ is a characteristic hallmark of Alzheimer’s disease and primarily participates in neurodegenerative pathologies. There has been no breakthrough made in the therapeutic regime of Alzheimer’s disease while the pharmacological interventions against Aβ are designed to sequester and clear Aβ burden from the neurological tissues. Based on the physiological relevance of Aβ, therapeutic approaches are required to inhibit and stabilize Aβ fibrillization, instead of cleaning it from the neurological system. In this context, we have designed a selenadiazole-based library of compounds against the fibrillization paradigm of Aβ. Compounds that completely inhibited the Aβ fibrillization appeared to stabilize Aβ at the monomeric stage as indicated by ThT assay, CD spectrophotometry, and TEM imaging. Partial inhibitors elongated the nucleation phase and allowed limited fibrillization of Aβ into smaller fragments with slightly higher β-sheets contents, while noninhibitors did not interfere in Aβ aggregation and resulted in mature fibrils with fibrillization kinetics similar to Aβ control. Molecular docking revealed the different binding positions of the compounds for three classes. Complete inhibitors alleviated Aβ toxicity to SH-SY5Y neuroblastoma cells and permeated across the blood-brain barrier in zebrafish larvae. The amino acid residues from Aβ peptide that interacted with the compounds from all three classes were overlapping and majorly lying in the amyloidogenic regions. However, compounds that stabilize Aβ monomers displayed higher association constants (K a) and lower dissociation constants (K d) in comparison to partial and noninhibitors, as corroborated by ITC. These results support further structure activity-based preclinical development of these selenadiazole compounds for potential anti-Alzheimer’s therapy.

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“…Second, screen natural substances with multiple actions against various insults/mechanisms involved in AD. Several natural compounds, such as chelerythrine ( Marasco et al, 2021 ), chalcone ( Thapa et al, 2021 ), coumarin ( Li et al, 2022 ), huprine ( Serrano et al, 2016 ), curcumin ( Mukherjee et al, 2021 ), rhein ( Li et al, 2019 ), berberine ( Akbar et al, 2021 ), and resveratrol derivatives ( Akbar et al, 2021 ), have shown such potential and warrant further studies for AD drug development ( Noori et al, 2021 ). The new drug GV-971 ( Xiao et al, 2021 ) belongs to this category.…”

Section: Multi-targets: An Unconventional Strategy For Alzheimer’s Di...mentioning

confidence: 99%

Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer’s Disease

Chen

Dai

Liu

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Despite the enormous amounts of resources and efforts for AD drug development during the last three decades, no effective treatments have been developed that can slow or halt the progression of the disease. Currently available drugs for treating AD can only improve clinical symptoms temporarily with moderate efficacies. In recent years, the scientific community has realized these challenges and reconsidered the future directions of AD drug development. The most significant recent changes in AD drug development strategy include shifting from amyloid-based targets to other targets, such as tau, and efforts toward better designs for clinical trials. However, most AD drug development is still focused on a single mechanism or target, which is the conventional strategy for drug development. Although multifactorial mechanisms and, on this basis, multi-target strategies have been proposed in recent years, this approach has not been widely recognized and accepted by the mainstream of AD drug development. Here, we emphasize the multifactorial mechanisms of AD and discuss the urgent need for a paradigm shift in AD drug development from a single target to multiple targets, either with the multi-target–directed ligands approach or the combination therapy approach. We hope this article will increase the recognition of the multifactorial nature of AD and promote this paradigm shift. We believe that such a shift will facilitate successful development of effective AD therapies.

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Plant isoquinoline alkaloids as potential neurodrugs: A comparative study of the effects of benzo[c]phenanthridine and berberine-based compounds on β-amyloid aggregation

Cited by 32 publications

References 102 publications

Natural Alkaloid Compounds as Inhibitors for Alpha-Synuclein Seeded Fibril Formation and Toxicity

Natural Alkaloid Compounds as Inhibitors for Alpha-Synuclein Seeded Fibril Formation and Toxicity

Structure Dependent Differential Modulation of Aβ Fibrillization by Selenadiazole-Based Inhibitors

Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer’s Disease

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