HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity

Abstract

Amyloid deposits of misfolded amyloid-β protein (Aβ) on neuronal cells are a pathological hallmark of Alzheimer's disease (AD). Prevention of the abnormal Aβ aggregation has been considered as a promising therapeutic strategy for AD treatment. To prevent reinventing the wheel, we proposed to search the existing drug database for other diseases to identify potential Aβ inhibitors. Herein, we reported the inhibitory activity of HP-β-cyclodextrin (HP-β-CD), a well-known sugar used in drug delivery, genetic vector, environmental protection and treatment of Niemann-Pick disease type C1 (NPC1), against Aβ1-42 aggregation and Aβ-induced toxicity, with the aim of adding a new function as a sugar-based Aβ inhibitor. Experimental data showed that HP-β-CD molecules were not only nontoxic to cells, but also greatly inhibited Aβ fibrillization and reduced Aβ-induced toxicity in a concentration-dependent manner. At an optimal molar ratio of Aβ : HP-β-CD = 1 : 2, HP-β-CD enabled the reduction of 60% of Aβ fibrils and increased the cell viability to 92%. Such concentration-dependent inhibitor capacity of HP-β-CD was likely attributed to several combined effects, including the enhancement of Aβ-HP-β-CD interactions, prevention of structural transition of Aβ peptides towards β-sheet structures, and reduction of self-aggregation of HP-β-CD. In parallel, molecular simulations further revealed the atomic details of HP-β-CD interacting with the Aβ oligomer, showing that HP-β-CD had a high tendency to interact with hydrophobic residues of Aβ in two β-strands and the N-terminal tail. More importantly, we identified that the inner hydrophobic cavity of HP-β-CD was a key active site for Aβ inhibition. Once the inner cavity of HP-β-CD was blocked by a small hydrophobic molecule of ferulic acid, HP-β-CD completely lost its inhibition capacity against Aβ. Given the already established pharmaceutical functions of HP-β-CD in drug delivery, our findings suggest that HP-β-CD has great potential to be designed as a sugar-based Aβ inhibitor.

Development and In Vitro Evaluation of an Innovative “Dietary Flavonoid Supplement” on Osteoarthritis Process

“…This behavior can lead to increased in vivo ERT release and to the improvement of its bioavailability and activity. In addition, according to the literature [19, 20], an intrinsic activity of HP-betaCD on GAGs restoration also emerges, indicating its potential function in the treatment and prevention of many diseases associated with the imbalance of GAGs.…”

“…HP-betaCD is a soluble derivative of β -cyclodextrin and was selected because in the literature it is reported that it forms inclusion complexes with flavonoids and enhances their aqueous water solubility and dissolution rate [16–18]. Moreover, HP-betaCD appears to be useful in many diseases correlated to an increase of GAGs [19, 20], with PG also involved in OA.…”

A fehérje–ciklodextrin kölcsönhatás terápiás és diagnosztikai jelentősége

“…Az amyloid peptidek aggregációjának gátlására több ciklodextrin-féleséget is teszteltek. 14 A leghatékonyabb in vitro aggregáció gátlást -koncentrácófüggõ módon -a hidroxipropil-béta-CD (HPBCD) mutatta. (7. ábra) 7.…”

“…ábra AFM felvételek amyloid beta-peptid aggregációjáról HPBCD jelenlétében 5-10-20 órás inkubáció után. 14 A bíztató in vitro eredményt követõen a Weil Cornell egyetem kutatói igazolták, hogy a HPBCD származék amyloid aggregációt gátló hatása in vivo is jelentkezik. 15 …”

Supramolecular Pharmaceutical Sciences: A Novel Concept Combining Pharmaceutical Sciences and Supramolecular Chemistry with a Focus on Cyclodextrin-Based Supermolecules

“…Recently, various bioactivities of CyDs have been demonstrated, and CyDs have been used as active pharmaceutical ingredients (APIs) against Niemann-Pick disease type C (NPC), [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] leukemia, 77) hyperlipidemia, 78) Alzheimer's disease, [79][80][81][82][83][84] cerebral ischemic injury, 85) atherosclerosis, 86) diabetic kidney disease, 87) chronic renal failure, 88) AIDS, 89,90) influenza, 91) peripheral artery disease, 92) sterility, [93][94][95] solid cancers, [96][97][98][99][100][101] bacterial growth, 102) α-synucleinopathy, 103) GM1-gangliosidosis, 104) septic shock, [105][106][107] hypervitaminosis, 108) and transthyretin-related familial amyloidotic polyneuropathy (FAP) …”