Advances of metallodrug-amyloid β aggregation inhibitors for therapeutic intervention in neurodegenerative diseases: Evaluation of their mechanistic insights and neurotoxicity

Yasir Khan, Huzaifa; Ahmad, Azeem; Nadir Hassan, Md; Hasan Khan, Yassir; Arjmand, Farukh; Hasan Khan, Rizwan

doi:10.1016/j.ccr.2023.215580

Cited by 8 publications

(1 citation statement)

References 155 publications

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“…In the field of drug discovery, various Aβ-targeting agents, e.g., small molecules, − peptides, proteins, , monoclonal antibodies, metallodrugs, − and nanomaterials, − have been validated for positive results for inhibiting Aβ fibrillization. Recently, it has been reported that endogenous proteins including transthyretin (TTR), apolipoprotein E, clusterin, and BRICHOS protein, can impede amyloid formation by regulating the protein homeostasis, showing the potential for therapeutic applications.…”

Section: Introductionmentioning

confidence: 99%

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

Wang,

Liu,

Sun

et al. 2024

Bioconjugate Chem.

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The design of a potent amyloid-β protein (Aβ) inhibitor plays a pivotal role in the prevention and treatment of Alzheimer’s disease (AD). Despite endogenous transthyretin (TTR) being recognized as an Aβ inhibitor, the weak inhibitory and blood brain barrier (BBB) crossing capabilities hinder it for Aβ aggregation inhibition and transport. Therefore, we have herein designed a recombinant TTR by conjugating a cationic cell penetrating peptide (penetratin, Pen), which not only enabled the fusion protein, TTR-Pen (TP), to present high BBB penetration but also greatly enhanced the potency of Aβ inhibition. Namely, the protein fusion made TP positively charged, leading to a potent suppression of Aβ40 fibrillization at a low concentration (1.5 μM), while a TTR concentration as high as 12.5 μM was required to gain a similar function. Moreover, TP could mitigate Aβ-induced neuronal death, increase cultured cell viability from 72% to 92% at 2.5 μM, and extend the lifespan of AD nematodes from 14 to 18 d. Thermodynamic studies revealed that TP, enriched in positive charges, presented extensive electrostatic interactions with Aβ40. Importantly, TP showed excellent BBB penetration performance, with a 10 times higher BBB permeability than TTR, which would allow TP to enter the brain of AD patients and participate in the transport of Aβ species out of the brain. Thus, it is expected that the fusion protein has great potential for drug development in AD treatment.

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Section: Introductionmentioning

confidence: 99%

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

Wang,

Liu,

Sun

et al. 2024

Bioconjugate Chem.

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Transition Metal Complexes as Therapeutics: A New Frontier in Combatting Neurodegenerative Disorders through Protein Aggregation Modulation

Navale,

Ahmed,

Lim

et al. 2024

Adv Healthcare Materials

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Neurodegenerative disorders (NDDs) are a class of debilitating diseases that progressively impair the protein structure and result in neurological dysfunction in the nervous system. Among these disorders, Alzheimer's disease (AD), prion diseases such as Creutzfeldt‐Jakob disease (CJD), and Parkinson's disease (PD) are caused by protein misfolding and aggregation at the cellular level. In recent years, transition metal complexes have gained significant attention for their potential applications in diagnosing, imaging, and curing these NDDs. These complexes have intriguing possibilities as therapeutics due to their diverse ligand systems and chemical properties and can interact with biological systems with minimal detrimental effects. This review focuses on the recent progress in transition metal therapeutics as a new era of hope in the battle against AD, CJD, and PD by modulating protein aggregation in vitro and in vivo. It may shed revolutionary insights into unlocking new opportunities for researchers to develop metal‐based drugs to combat NDDs.

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Platinum (II) Schiff Base Complexes and their Effects on the Inhibition of Amyloid β_1–42 Aggregation

İrişli,

Günnaz,

Özcan

et al. 2024

Applied Organom Chemis

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For synthesizing metal–organic molecules with pro‐drug properties to prevent the accumulation of amyloid beta (Aβ1–42), which is a feature of neurodegenerative Alzheimer's disease, two new Schiff bases with imine/amine donors 2‐([3,3‐diphenylalidene]amino)‐N,N‐dimethylethane‐1‐amine and N,N‐dimethyl‐2‐([quinolin‐4‐ylmethylene]amino)ethane‐1‐amine, as well as their novel Pt (II) complexes (I and II), were synthesized and characterized via Fourier transform infrared spectroscopy, 1H‐ and 13C‐nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and elemental analyses. The spectroscopic data has shown that the ligands are coordinated to the central atom in a chelating manner.Furthermore, the interaction between these complexes and Aβ1–42 was investigated using the electrochemical methods, square wave voltammetry and pencil graphite electrode, while monitoring the changes in the oxidation signal of the Try residue in Aβ1–42.The ability of the compounds to inhibit Aβ1–42 aggregation was investigated using the human neuroblastoma cell line (SH‐SY5Y). Complex II could actively inhibit the aggregation of Aβ1–42 at a molar ratio of 1.0/1.0, and its Aβ1–42 aggregation kinetics were fluorometrically determined using thioflavin T.These results were supported by scanning electron microscopy and transmission electron microscopy analyses. Moreover, the interaction of complex II with Aβ1–16 was investigated via 1H‐NMR spectroscopy.As a result, it was observed that complex II was effective in inhibiting the aggregation of Aβ1–42 at a molar ratio of 1.0/1.0. This result shows that studies can be conducted on the effects of Schiff base‐Pt complexes as potential pro‐drugs on Alzheimer's disease.

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Advances of metallodrug-amyloid β aggregation inhibitors for therapeutic intervention in neurodegenerative diseases: Evaluation of their mechanistic insights and neurotoxicity

Cited by 8 publications

References 155 publications

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

Transition Metal Complexes as Therapeutics: A New Frontier in Combatting Neurodegenerative Disorders through Protein Aggregation Modulation

Platinum (II) Schiff Base Complexes and their Effects on the Inhibition of Amyloid β_1–42 Aggregation

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Advances of metallodrug-amyloid β aggregation inhibitors for therapeutic intervention in neurodegenerative diseases: Evaluation of their mechanistic insights and neurotoxicity

Cited by 8 publications

References 155 publications

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

Transthyretin-Penetratin: A Potent Fusion Protein Inhibitor against Alzheimer’s Amyloid-β Fibrillogenesis with High Blood Brain Barrier Crossing Capability

Transition Metal Complexes as Therapeutics: A New Frontier in Combatting Neurodegenerative Disorders through Protein Aggregation Modulation

Platinum (II) Schiff Base Complexes and their Effects on the Inhibition of Amyloid β1–42 Aggregation

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Product

Resources

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Platinum (II) Schiff Base Complexes and their Effects on the Inhibition of Amyloid β_1–42 Aggregation