scholarly journals Exploring Charged Polymeric Cyclodextrins for Biomedical Applications

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1724
Author(s):  
Noemi Bognanni ◽  
Francesco Bellia ◽  
Maurizio Viale ◽  
Nadia Bertola ◽  
Graziella Vecchio
Keyword(s):  
Molecular Chaperones ◽  
Potential Application ◽  
Protein Misfolding ◽  
Biomedical Applications ◽  
Drug Carriers ◽  
Doxorubicin Toxicity ◽  
A2780 Cell ◽  
A2780 Cell Line ◽  
Cyclodextrin Polymers ◽  
Misfolding Diseases

Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of β- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid β peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.

scholarly journals Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly

2020 ◽  
Vol 21 (23) ◽  
pp. 9186
Author(s):  
Rubén Hervás ◽  
Javier Oroz
Keyword(s):  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Protective Role ◽  
Soluble Proteins ◽  
Protein Deposits ◽  
Client Proteins ◽  
Recognition Motifs ◽  
Misfolding Diseases

Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.

Roles of molecular chaperones in protein misfolding diseases

2004 ◽  
Vol 15 (1) ◽  
pp. 17-29 ◽  
Author(s):  
José M Barral ◽  
Sarah A Broadley ◽  
Gregor Schaffar ◽  
F.Ulrich Hartl
Keyword(s):  
Molecular Chaperones ◽  
Protein Misfolding ◽  
Misfolding Diseases

scholarly journals Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Aβ42 oligomers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Francesco Simone Ruggeri ◽  
Johnny Habchi ◽  
Sean Chia ◽  
Robert I. Horne ◽  
Michele Vendruscolo ◽  
...  
Keyword(s):  
Small Molecules ◽  
Single Molecule ◽  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Chemical Sensitivity ◽  
Incomplete Knowledge ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitor ◽  
Misfolding Diseases

AbstractSignificant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer’s and Parkinson’s diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer’s disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases.

scholarly journals Preparation and Sustained-Release Performance of PLGA Microcapsule Carrier System

Nanomaterials ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1758
Author(s):  
Shuaikai Ren ◽  
Chunxin Wang ◽  
Liang Guo ◽  
Congcong Xu ◽  
Yan Wang ◽  
...  
Keyword(s):  
Controlled Release ◽  
Biomedical Applications ◽  
Encapsulation Efficiency ◽  
Drug Carriers ◽  
Optimum Conditions ◽  
Carrier System ◽  
Preparation Conditions ◽  
Encapsulation Rate ◽  
Release Drug ◽  
Release Curve

Microcapsules have been widely studied owing to their biocompatibility and potential for application in various areas, particularly drug delivery. However, the size of microcapsules is difficult to control, and the size distribution is very broad via various encapsulation techniques. Therefore, it is necessary to obtain microcapsules with uniform and tailored size for the construction of controlled-release drug carriers. In this study, emulsification and solvent evaporation methods were used to prepare a variety of ovalbumin-loaded poly (lactic-co-glycolic acid) (PLGA) microcapsules to determine the optimal preparation conditions. The particle size of the PLGA microcapsules prepared using the optimum conditions was approximately 200 nm, which showed good dispersibility with an ovalbumin encapsulation rate of more than 60%. In addition, porous microcapsules with different pore sizes were prepared by adding a varying amount of porogen bovine serum albumin (BSA) to the internal water phase. The release curve showed that the rate of protein release from the microcapsules could be controlled by adjusting the pore size. These findings demonstrated that we could tailor the morphology and structure of microcapsules by regulating the preparation conditions, thus controlling the encapsulation efficiency and the release performance of the microcapsule carrier system. We envision that this controlled-release novel microcapsule carrier system shows great potential for biomedical applications.

Synthesis and evaluation of second generation Flex-Het scaffolds against the human ovarian cancer A2780 cell line

2015 ◽  
Vol 96 ◽  
pp. 209-217 ◽  
Author(s):  
Krishna Kumar Gnanasekaran ◽  
Doris Mangiaracina Benbrook ◽  
Baskar Nammalwar ◽  
Elangovan Thavathiru ◽  
Richard A. Bunce ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Line ◽  
Second Generation ◽  
Human Ovarian Cancer ◽  
A2780 Cell ◽  
A2780 Cell Line

scholarly journals SAR by kinetics for drug discovery in protein misfolding diseases

2018 ◽  
Vol 115 (41) ◽  
pp. 10245-10250 ◽  
Author(s):  
Sean Chia ◽  
Johnny Habchi ◽  
Thomas C. T. Michaels ◽  
Samuel I. A. Cohen ◽  
Sara Linse ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Misfolding ◽  
Amyloid Beta Peptide ◽  
Oligomer Formation ◽  
Chemical Derivatives ◽  
Structure Activity ◽  
Beta Peptide ◽  
Misfolding Diseases ◽  
Aβ Oligomer

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

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