Carrier-free self-built aspirin nanorods as anti-aggregation agents towards alpha-crystallin-derived peptide aggregates: potential implications in non-invasive cataract therapy

Bisht, Anjali; Sharma, Manju; Sharma, Sucheta; Ali, Md. Ehesan; Panda, Jiban Jyoti

doi:10.1039/c9tb01435g

Cited by 13 publications

(3 citation statements)

References 35 publications

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“…Attempts to treat α-crystallin-associated cataract typically focus on resolubilizing the protein, as protein turnover in the lens is negligible and so degradation is not a viable option. Aspirin nanorods have shown effectiveness in maintaining α-crystallin solubility in vitro, allowing for the possibility of an aspirin-based cataract treatment (143). Mouse models of hereditary and agerelated cataract have been successfully treated with small molecules; one compound in particular, 5-cholesten-3b,25-diol, improves the solubility of α-crystallin by 63% (144).…”

Section: Human α-Crystallin Chaperone Activity As a Biomedical And Th...mentioning

confidence: 99%

α-Crystallins in the Vertebrate Eye Lens: Complex Oligomers and Molecular Chaperones

Sprague-Piercy

Rocha

Kwok

et al. 2021

Annu. Rev. Phys. Chem.

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α-Crystallins are small heat-shock proteins that act as holdase chaperones. In humans, αA-crystallin is expressed only in the eye lens, while αB-crystallin is found in many tissues. α-Crystallins have a central domain flanked by flexible extensions and form dynamic, heterogeneous oligomers. Structural models show that both the C- and N-terminal extensions are important for controlling oligomerization through domain swapping. α-Crystallin prevents aggregation of damaged β- and γ-crystallins by binding to the client protein using a variety of binding modes. α-Crystallin chaperone activity can be compromised by mutation or posttranslational modifications, leading to protein aggregation and cataract. Because of their high solubility and their ability to form large, functional oligomers, α-crystallins are particularly amenable to structure determination by solid-state NMR and solution NMR, as well as cryo-electron microscopy. Expected final online publication date for the Annual Review of Physical Chemistry, Volume 72 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Human α-Crystallin Chaperone Activity As a Biomedical And Th...mentioning

confidence: 99%

α-Crystallins in the Vertebrate Eye Lens: Complex Oligomers and Molecular Chaperones

Sprague-Piercy

Rocha

Kwok

et al. 2021

Annu. Rev. Phys. Chem.

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“…36,37 A large number of PfK13 mutations have been associated with artemisinin resistance, 19,21,26 however, it is not yet known why do these specific mutations instigate drug resistance. In this work, we have investigated the structural dynamics of PfK13 wild-type (WT) and four mutant protein structures by adopting the classical molecular dynamic simulations [38][39][40] to address the issue and established a correlation of the protein dynamics with the artemisinin drug resistance.…”

Section: Introductionmentioning

confidence: 99%

How do the Mutations in PfK13 Protein Promote Anti-malarial Drug Resistance?

Sharma¹,

Ali²

2022

Preprint

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Plasmodium falciparum develops resistance to artemisinin upon exposure to the anti-malarial drug. Various mutations in the Plasmodium falciparum Kelch13 (PfK13) protein such as Y493H, R539T, I543T, and C580Y have been associated with antimalarial drug resistance. (Ariey et al., Nature, 2014, 505, 50-55) These mutations impede the regular ubiquitination process that eventually invokes drug resistance. However, the relationship between the mutation and the mechanism of drug resistance has not yet been fully elucidated. The comparative protein dynamics are studied by performing the classical molecular dynamics (MD) simulations and subsequent analysis of the trajectories adopting root-means-square fluctuations, the secondary-structure predictions and the dynamical cross-correlation matrix analysis tools. Here we observed that the mutations in the Kelch-domain does not have any structural impact on the mutated site, however, it significantly alters the overall dynamics of the protein. The loop-region of the BTB-domain especially for Y493H and C580Y mutants are found to have the enhanced dynamical fluctuations. The enhanced fluctuations in the BTB-domain could affect the protein-protein (PfK13-Cullin) binding interactions in the ubiquitination process and eventually leads to anti-malarial drug resistance.

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“…During the last two decades, as a simple and promising strategy to construct well-ordered nanostructures, the supramolecular self-assembly (SSA) system for drug delivery relying on a “bottom-up” approach has aroused more and more attention. − In the system, the multiple noncovalent forces, such as electrostatic interaction, hydrogen bonds, hydrophobic effect, π–π stacking, van der Waals forces, host–guest interactions, and coordination bonds, can make drug molecules and other functionalized units array spontaneously into stable and ordered nanostructures with a certain geometric appearance including sphere, tube, fiber, lamellae, and so on. − The formed nanostructures with different morphologies and sizes are quite different from the parent drugs or a simple mixture of drugs in physicochemical properties and biology functions. − More importantly, with the help of reversible, controllable, and dynamic noncovalent interactions as driving forces, the drug delivery based on SSA can fulfill the precise control of components at the molecular level and provide easy-to-adjust morphologies and sizes of self-assembled structures to adapt well to the application environment. − Due to these distinct merits, this strategy has been preliminarily applied to the formulation design of pesticides. In our previous work, self-assembled nanoparticles (NPs) based on the fungicides fenhexamid and polyhexamethylene biguanide were constructed for achieving desirable physicochemical properties and a strong synergistic effect on the antimicrobial activity .…”

mentioning

confidence: 99%

Supramolecular Self-Assembly of Herbicides with Reduced Risks to the Environment

et al. 2022

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The side effects caused by some pesticides with high off-target movement have brought great risks to the environment and human health. Here, taking 2,4-dichlorophenoxyacetic acid (2,4-D) as a model herbicide to reduce its volatilization and leaching, a supramolecular self-assembly mediated by branched polyethylenimine (B-PEI) was constructed through noncovalent molecular recognition. The results showed that 2,4-D/B-PEI nanoparticles (NPs) with a mean particle size of 168 nm can be formed by electrostatic interaction, hydrophobic effect, and π–π stacking when the mass ratio of 2,4-D to B-PEI with the average molecular weight of 10 000 (B-PEI 10k) was 40:20, and their generation was not susceptible to common inorganic ions such as Ca2+, Na+, Cl–, and SO4 2–. Compared with 2,4-D, the self-assembled NPs with improved physicochemical properties including strong positive charges (+58.2 mV), reduced volatilization rate (2.50%), low surface tension (56.10 mN m–1), and decreased leaching potential could minimize the adverse impacts of this herbicide on the environment. The biological activity experiments in the greenhouse and field demonstrated that the control efficacy of NPs without using any surfactant against weeds was almost the same as that of the 2,4-D sodium salt form containing Tween 80. The safety tests showed that the self-assembled NPs had the same genotoxicity as 2,4-D to Vicia faba and little effect on the soil enzyme activities. Overall, the development of self-assembled herbicidal nanoformulations with desirable physicochemical properties and low risks to the environment would have potential application in agricultural production.

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Carrier-free self-built aspirin nanorods as anti-aggregation agents towards alpha-crystallin-derived peptide aggregates: potential implications in non-invasive cataract therapy

Abstract: Carrier free self-built aspirin nanorods as anti-aggregating agents for model crystallin peptides.

Cited by 13 publications

References 35 publications

α-Crystallins in the Vertebrate Eye Lens: Complex Oligomers and Molecular Chaperones

α-Crystallins in the Vertebrate Eye Lens: Complex Oligomers and Molecular Chaperones

How do the Mutations in PfK13 Protein Promote Anti-malarial Drug Resistance?

Supramolecular Self-Assembly of Herbicides with Reduced Risks to the Environment

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