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Korshavn, Kyle J.,Bhunia, Anirban,Lim, Mi Hee,Ramamoorthy, Ayyalusamy The Royal Society of Chemistry 2016 Chemical communications Vol.52 No.5
<P>Aggregation at the neuronal cell membrane's lipid bilayer surface is implicated in amyloid-beta (Ab) toxicity associated with Alzheimer's disease; however, structural and mechanistic insights into the process remain scarce. We have identified a conserved binding mode of A beta(40) on lipid bilayer surfaces with a conserved helix containing the self-recognition site (K16-E22).</P>
Cholesterol and metal ions in Alzheimer's disease
Lee, Hyuck Jin,Korshavn, Kyle J.,Kochi, Akiko,Derrick, Jeffrey S.,Lim, Mi Hee The Royal Society of Chemistry 2014 Chemical Society reviews Vol.43 No.19
<P>Cholesterol and metal ions have been suggested to be associated with the onset and progression of Alzheimer's disease (AD). Moreover, recent findings have demonstrated a potential interconnection between these two factors. For example, (a) cholesterol has been shown to be misregulated in AD-afflicted brains, and the aberrant activity of proteins (particularly, apolipoprotein E (ApoE) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)) has been linked to cholesterol-related AD exacerbation; (b) dyshomeostasis of metal ions associated with misfolded proteins (<I>i.e.</I>, amyloid-β (Aβ) aggregates) found in the brains of AD patients is shown to promote oxidative stress leading to the malfunction of multiple proteins, including cytochrome <I>c</I> oxidase (C<I>c</I>O), and Cu/Zn superoxide dismutase (SOD1); (c) metal ion misregulation has also been observed to disrupt the activity of proteins (<I>e.g.</I>, HMGR, low-density lipoproteins (LDL)), required for cholesterol production and regulation. Herein, we briefly discuss the potential involvement of cholesterol and metal ions in AD neuropathogenesis in both individual and interrelated manners.</P> <P>Graphic Abstract</P><P>This review describes the possible involvement of cholesterol and metal ions in AD neuropathogenesis in both individual and interconnected manners. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c4cs00005f'> </P>
Derrick, Jeffrey S.,Kerr, Richard A.,Korshavn, Kyle J.,McLane, Michael J.,Kang, Juhye,Nam, Eunju,Ramamoorthy, Ayyalusamy,Ruotolo, Brandon T.,Lim, Mi Hee American Chemical Society 2016 Inorganic Chemistry Vol.55 No.10
<P>The complex and multifaceted pathology of Alzheimer's disease (AD) continues to present a formidable challenge to the establishment of long-term treatment strategies. Multifunctional compounds able to modulate the reactivities of various pathological features, such as amyloid-beta (A beta) aggregation, metal ion dyshomeostasis, and oxidative stress, have emerged as useful tactic. Recently, an incorporation approach to the rational design of multipurpose small molecules has been validated through the production of a multifunctional ligand (ML) as a potential chemical tool for AD. In order to further the development of more diverse and improved multifunctional reagents, essential pharmacophores must be identified. Herein, we report a series of aminoquinoline derivatives (AQ1-4, AQP1-4, and AQDA1-3) based on ML's framework, prepared to gain a structure reactivity understanding of ML's multifunctionality in addition to tuning its metal binding affinity. Our structure reactivity investigations have implicated the dimethylamino group as a key component for supplying the antiamyloidogenic characteristics of ML in both the absence and presence of metal ions. Two-dimensional NMR studies indicate that structural variations of ML could tune its interaction sites along the A beta sequence. In addition, mass spectrometric analyses suggest that the ability of our aminoquinoline derivatives to regulate metal-induced A beta aggregation may be influenced by their metal binding properties. Moreover, structural modifications to ML were also observed to noticeably change its metal binding affinities and metal-to-ligand stoichiometries that were shown to be linked to their antiamyloidogenic and antioxidant activities. Overall, our studies provide new insights into rational design strategies for multifunctional ligands directed at regulating metal ions, A beta, and oxidative stress in AD and could advance the development of improved next-generation multifunctional reagents.</P>
Multi-target-directed phenol–triazole ligands as therapeutic agents for Alzheimer's disease
Jones, Michael R.,Mathieu, Emilie,Dyrager, Christine,Faissner, Simon,Vaillancourt, Zavier,Korshavn, Kyle J.,Lim, Mi Hee,Ramamoorthy, Ayyalusamy,Wee Yong, V.,Tsutsui, Shigeki,Stys, Peter K.,Storr, Tim Royal Society of Chemistry 2017 Chemical Science Vol.8 No.8
<▼1><P>A series of multi-target-directed ligands are described that bind Cu, act as antioxidants, modulate Aβ peptide aggregation, and abolish Aβ toxicity in primary neurons.</P></▼1><▼2><P>Alzheimer's disease (AD) is a multifactorial disease that is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid-β (Aβ) plaque deposits. Increased oxidative stress, metal ion dysregulation, and the formation of toxic Aβ peptide oligomers are all considered to contribute to the etiology of AD. In this work we have developed a series of ligands that are multi-target-directed in order to address several disease properties. 2-(1-(3-Hydroxypropyl)-1<I>H</I>-1,2,3-triazol-4-yl)phenol (<B>POH</B>), 2-(1-(2-morpholinoethyl)-1<I>H</I>-1,2,3-triazol-4-yl)phenol (<B>PMorph</B>), and 2-(1-(2-thiomorpholinoethyl)-1<I>H</I>-1,2,3-triazol-4-yl)phenol (<B>PTMorph</B>) have been synthesized and screened for their antioxidant capacity, Cu-binding affinity, interaction with the Aβ peptide and modulation of Aβ peptide aggregation, and the ability to limit Aβ<SUB>1–42</SUB>-induced neurotoxicity in human neuronal culture. The synthetic protocol and structural variance incorporated <I>via</I> click chemistry, highlights the influence of R-group modification on ligand-Aβ interactions and neuroprotective effects. Overall, this study demonstrates that the phenol–triazole ligand scaffold can target multiple factors associated with AD, thus warranting further therapeutic development.</P></▼2>